Cyano anthranilamide insecticides

ABSTRACT

This invention provides compounds of Formula 1, N-oxides and suitable salts thereof 
                         
wherein
         R 1  is Me, Cl, Br or F;   R 2  is F, Cl, Br, C 1 -C 4  haloalkyl or C 1 -C 4  haloalkoxy;   R 3  is F, Cl or Br;   R 4  is H; C 1 -C 4  alkyl, C 3 -C 4  alkenyl, C 3 -C 4  alkynyl, C 3 -C 5  cycloalkyl, or C 4 -C 6  cycloalkylalkyl, each optionally substituted with one substituent selected from the group consisting of halogen, CN, SMe, S(O)Me, S(O) 2 Me, and OMe;   R 5  is H or Me;   R 6  is H, F or Cl; and   R 7  is H, F or Cl.
 
Also disclosed are methods for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Formula 1, an N-oxide thereof or a suitable salt of the compound (e.g., as a composition described herein). This invention also pertains to a composition for controlling an invertebrate pest comprising a biologically effective amount of a compound of Formula 1, an N-oxide thereof or a suitable salt of the compound and at least one additional component selected from the group consisting of a surfactant, a solid diluent and a liquid diluent.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 11/811,105,filed Jun. 8, 2007, now U.S. Pat. No. 7,875,634, which is a division ofU.S. application Ser. No. 10/540,966, filed on Jun. 29, 2005, now U.S.Pat. No. 7,247,647, which is a 371 national stage entry ofPCT/US2004/003568, internationally filed on Jan. 21, 2004, which claimspriority from U.S. Provisional Application No. 60/443,256, filed Jan.28, 2003.

FIELD OF THE INVENTION

This invention relates to certain anthranilamides, their N-oxides, saltsand compositions suitable for agronomic and nonagronomic uses, includingthose uses listed below, and a method of their use for controllinginvertebrate pests in both agronomic and nonagronomic environments.

BACKGROUND OF THE INVENTION

The control of invertebrate pests is extremely important in achievinghigh crop efficiency. Damage by invertebrate pests to growing and storedagronomic crops can cause significant reduction in productivity andthereby result in increased costs to the consumer. The control ofinvertebrate pests in forestry, greenhouse crops, ornamentals, nurserycrops, stored food and fiber products, livestock, household, and publicand animal health is also important. Many products are commerciallyavailable for these purposes, but the need continues for new compoundsthat are more effective, less costly, less toxic, environmentally saferor have different modes of action.

WO 01/070671 discloses N-acyl anthranilic acid derivatives of Formula ias arthropodicides

wherein, inter alia, A and B are independently O or S; J is anoptionally substituted phenyl ring, 5- or 6-membered heteroaromaticring, naphthyl ring system or an aromatic 8-, 9- or 10-membered fusedheterobicyclic ring system; R¹ and R³ are independently H or optionallysubstituted C₁-C₆ alkyl; R² is H or C₁-C₆ alkyl; each R⁴ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen or CN; and n is 1to 4.

SUMMARY OF THE INVENTION

This invention pertains to compounds of Formula 1, their N-oxides orsalts thereof

wherein

-   -   R¹ is Me, Cl, Br or F;    -   R² is F, Cl, Br, C₁-C₄ haloalkyl or C₁-C₄ haloalkoxy;    -   R³ is F, Cl or Br;    -   R⁴ is H; C₁-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₄ alkynyl, C₃-C₅        cycloalkyl, or C₄-C₆ cycloalkylalkyl, each optionally        substituted with one substituent selected from the group        consisting of halogen, CN, SMe, S(O)Me, S(O)₇Me, and OMe;    -   R⁵ is H or Me;    -   R⁶ is H, F or Cl; and    -   R⁷ is H, F or Cl.

This invention also pertains to a composition for controlling aninvertebrate pest comprising a biologically effective amount of acompound of Formula 1 and at least one additional component selectedfrom the group consisting of a surfactant, a solid diluent and liquiddiluent and optionally an effective amount of at least one additionalbiologically active compound or agent.

This invention also pertains to a method for controlling an invertebratepest comprising contacting the invertebrate pest or its environment witha biologically effective amount of a compound of Formula 1 (e.g., as acomposition described herein). This invention also relates to a methodfor controlling an invertebrate pest comprising contacting theinvertebrate pest or its environment with a biologically effectiveamount of a composition comprising a biologically effective amount of acompound of Formula 1 and at least one additional component selectedfrom the group consisting of a surfactant, a solid diluent and a liquiddiluent, said composition optionally further comprising an effectiveamount of a of at least one additional biologically active compound oragent.

This invention further pertains to a spray composition comprising acompound of Formula 1 and a propellant, and to a bait compositioncomprising a compound of Formula 1, one or more food materials, anoptional attractant, and an optional humectant. This invention alsopertains to a device for controlling an invertebrate pest comprisingsaid bait composition and a housing adapted to receive the baitcomposition, wherein the housing has at least one opening sized topermit the invertebrate pest to pass through the opening so theinvertebrate pest can gain access to the bait composition from alocation outside the housing and wherein the housing is further adaptedto be placed in or near a locus of potential or known activity for theinvertebrate pest.

DETAILS OF THE INVENTION

In the above recitations, the term “alkyl”, used either alone or incompound words such as “alkylthio” or “haloalkyl” includesstraight-chain or branched alkyl, such as, methyl, ethyl, n-propyl,i-propyl, or the different butyl isomers. The term “halogen”, eitheralone or in compound words such as “haloalkoxy”, includes fluorine,chlorine, bromine or iodine. Further, when used in compound words suchas “haloalkyl”, or “haloalkoxy”, said alkyl or alkoxy may be partiallyor fully substituted with halogen atoms which may be the same ordifferent. Examples of “haloalkyl” include F₃C, ClCH₂, CF₃CH₂ andCF₃CCl₂. Examples of “haloalkoxy” include CF₃O, HCF₂O, CCl₃CH₂O,HCF₂CH₂CH₂O and CF₃CH₂O.

One skilled in the art will appreciate that not all nitrogen-containingheterocycles can form N-oxides since the nitrogen requires an availablelone pair for oxidation to the oxide; one skilled in the art willrecognize those nitrogen-containing heterocycles which can formN-oxides. One skilled in the art will also recognize that tertiaryamines can form N-oxides. Synthetic methods for the preparation ofN-oxides of heterocycles and tertiary amines are very well known by oneskilled in the art including the oxidation of heterocycles and tertiaryamines with peroxy acids such as peracetic and m-chloroperbenzoic acid(MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butylhydroperoxide, sodium perborate, and dioxiranes such asdimethydroxirane. These methods for the preparation of N-oxides havebeen extensively described and reviewed in the literature, see forexample: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik inComprehensive Heterocyclic Chemistry, 3, pp 18-20, A. J. Boulton and A.McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene inAdvances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R.Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advancesin Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J.Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G.Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A.R. Katritzky and A. J. Boulton, Eds., Academic Press.

Compounds of this invention can exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. One skilled in the art will appreciate that onestereoisomer may be more active and/or may exhibit beneficial effectswhen enriched relative to the other stereoisomer(s) or when separatedfrom the other stereoisomer(s). Additionally, the skilled artisan knowshow to separate, enrich, and/or to selectively prepare saidstereoisomers. Accordingly, the present invention comprises compoundsselected from Formula 1, N-oxides and salts thereof. The compounds ofthe invention may be present as a mixture of stereoisomers, individualstereoisomers, or as an optically active form.

The salts of the compounds of the invention include acid-addition saltswith inorganic or organic acids such as hydrobromic, hydrochloric,nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic,malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic orvaleric acids. In the compositions and methods of this invention, thesalts of the compounds of the invention are preferably suitable for theagronomic and/or non-agronomic uses described herein.

Of note are compounds of Formula I wherein

-   -   R⁴ is H or C₁-C₄ alkyl optionally substituted with one        substituent selected from the group consisting of CN, SMe and        OMe;    -   R⁵ is H or Me;    -   R⁶ is H; and    -   R⁷ is H.    -   Preferred compounds for reasons of cost, ease of synthesis        and/or biological efficacy are:

Preferred 1. Compounds of Formula 1 wherein

-   -   R¹ is Me or Cl;    -   R² is Cl, Br, CF₃, OCF₂H, OCF₃ or OCH₂CF₃; and    -   R⁴ is H, Me, Et, i-Pr, t-Bu, CH₂CN, CH(Me)CH₂SMe or        C(Me)₂CH₂SMe.

Preferred 2. Compounds of Preferred 1 wherein

-   -   R² is Cl, Br, CF₃ or OCH₂CF₃;    -   R⁴ is H, Me, Et or i-Pr; and    -   R⁵ is H.

Of note are compounds of Preferred 1 and Preferred 2 wherein R⁶ is H;and R⁷ is H.

The preferred compositions of the present invention are those, whichcomprise the above preferred compounds. The preferred methods of use arethose involving the above-preferred compounds.

The compounds of Formula 1 can be prepared by one or more of thefollowing methods and variation as described in Schemes 1-20. Thedefinitions of R¹, R², R³, R⁴, and R⁵ in the compounds of Formulae 1-24below are as defined above in the Summary of the Invention unlessindicated otherwise.

Compounds of Formula 1 can be prepared by the reaction of benzoxazinonesof Formula 2 with an amine of Formula HNR⁴R⁵ as outlined in Scheme 1.This reaction can be run neat or in a variety of suitable solventsincluding tetrahydrofuran, diethyl ether, dioxane, toluene,dichloromethane or chloroform with optimum temperatures ranging fromroom temperature to the reflux temperature of the solvent. The generalreaction of benzoxazinones with amines to produce anthranilamides iswell documented in the chemical literature. For a review ofbenzoxazinone chemistry see Jakobsen et al., Biorganic and MedicinalChemistry 2000, 8, 2095-2103 and references cited within. See also G. M.Coppola, J. Heterocyclic Chemistry 1999, 36, 563-588.

Compounds of Formula 1 can also be prepared from haloanthranilicdiamides of Formula 3 (wherein X is halogen, preferably iodine orbromine) by the coupling method shown in Scheme 2. Reaction of acompound of Formula 3 with a metal cyanide (e.g. cuprous cyanide, zinccyanide, or potassium cyanide), optionally with or without a suitablepalladium catalyst [e.g. tetrakis(triphenylphosphine)palladium(0) ordichlorobis(triphenylphosphine) palladium(II)] and optionally with orwithout a metal halide (e.g. cuprous iodide, zinc iodide, or potassiumiodide) in a suitable solvent such as acetonitrile,N,N-dimethylformamide or N-methylpyrrolidinone, optionally attemperatures ranging from room temperature to the reflux temperature ofthe solvent, affords compounds of Formula 1. The suitable solvent canalso be tetrahydrofuran or dioxane when palladium catalyst is used inthe coupling reaction.

Cyanobenzoxazinones of Formula 2 can be prepared by the method outlinedin Scheme 3. Reaction of a halobenzoxazinone of Formula 4 (wherein X ishalogen, preferably iodine or bromine) with a metal cyanide using asimilar coupling method as described above for Scheme 2 (optionally withor without a palladium catalyst and optionally with or without a metalhalide present) affords a compound of Formula 2.

Cyanobenoxazinones of Formula 2 can also be prepared by the methoddetailed in Scheme 4 via coupling of a pyrazole carboxylic acid ofFormula 5 with a cyanoanthranilic acid of Formula 6. This reactioninvolves sequential addition of methanesulfonyl chloride in the presenceof a tertiary amine such as triethylamine or pyridine to a pyrazolecarboxylic acid of Formula 5, followed by the addition ofcyanoanthranilic acid of Formula 6, followed by a second addition oftertiary amine and methanesulfonyl chloride.

Scheme 5 depicts another method for preparing benzoxazinones of Formula2 involving coupling an isatoic anhydride of Formula 7 with a pyrazoleacid chloride of Formula 8. Solvents such as pyridine orpyridine/acetonitrile are suitable for this reaction. The acid chloridesof Formula 8 are available from the corresponding acids of Formula 5 byknown methods such as chlorination with thionyl chloride or oxalylchloride.

As shown in Scheme 6, haloanthranilic diamides of Formula 3 can beprepared by the reaction of benzoxazinones of Formula 4, wherein X ishalogen, with an amine of Formula HNR⁴R⁵ using a similar method asdescribed above for Scheme 1. Conditions for this reaction are similarto those specified in Scheme 1.

As shown in Scheme 7, halobenzoxazinones of Formula 4 (wherein X ishalogen) can be prepared via direct coupling of a pyridylpyrazolecarboxylic acid of Formula 5 with a haloanthranilic acid of Formula 9(wherein X is halogen) by a similar method as described above for Scheme4. This reaction involves sequential addition of methanesulfonylchloride in the presence of a tertiary amine such as triethylamine orpyridine to a pyrazolecarboxylic acid of Formula 5, followed by theaddition of a haloanthranilic acid of Formula 9, followed by a secondaddition of tertiary amine and methanesulfonyl chloride. This methodgenerally affords good yields of the benzoxazinone.

As shown in Scheme 8, a halobenzoxazinone of Formula 4 can also beprepared via coupling an isatoic anhydride of Formula 10 (wherein X ishalogen) with a pyrazole acid chloride of Formula 8 by a similar methodas described above for Scheme 5.

Cyanoanthranilic acids of Formula 6 can be prepared from haloanthranilicacids of Formula 9 as outlined in Scheme 9. Reaction of ahaloanthranilic acid of Formula 9 (wherein X is halogen) with a metalcyanide using the same coupling procedure described above for Scheme 2(optionally with or without a palladium catalyst and optionally with orwithout a metal halide present) affords a compound of Formula 6.

As illustrated in Scheme 10, cyanoisatoic anhydrides of Formula 7 can beprepared from cyanoanthranilic acids of Formula 6 by reaction withphosgene (or a phosgene equivalent such as triphosgene) or an alkylchloroformate (e.g. methyl chloroformate) in a suitable solvent such astoluene or tetrahydrofuran.

As shown in Scheme 11, haloanthranilic acids of Formula 9 can beprepared by direct halogenation of an unsubstituted anthranilic acid ofFormula 11 with N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) orN-iodosuccinimide (NIS) respectively in solvents such asN,N-dimethylformamide (DMF) to produce the correspondinghalogen-substituted acid of Formula 9.

As illustrated in Scheme 12, haloisatoic anhydrides of Formula 10 can beprepared from haloanthranilic acids of Formula 9 by reaction withphosgene (or a phosgene equivalent such as triphosgene) or an alkylchloroformate, e.g. methyl chloroformate, in a suitable solvent such astoluene or tetrahydrofuran.

Pyridylpyrazole carboxylic acids of Formula 5 can be prepared by themethod outlined in Scheme 13. Reaction of pyrazole 12 with a2-halopyridine of Formula 13 in the presence of a suitable base such aspotassium carbonate in a solvent such as N,N-dimethylformamide oracetonitrile affords good yields of the 1-pyridylpyrazole 14 with goodspecificity for the desired regiochemistry. Metallation of 14 withlithium diisopropylamide (LDA) followed by quenching of the lithium saltwith carbon dioxide affords the pyrazole carboxylic acid of Formula 5.

The starting pyrazoles 12 wherein R² is CF₃, Cl or Br are knowncompounds. Pyrazole 12 wherein R² is CF₃ can be prepared by literatureprocedures (J. Fluorine Chem. 1991, 53(1), 61-70). Pyrazoles 12 whereinR² is Cl or Br can also be prepared by literature procedures (H.Reimlinger and A. Van Overstraeten, Chem. Ber. 1966, 99(10), 3350-7). Auseful alternative method for the preparation of 12 wherein R² is Cl orBr is depicted in Scheme 14. Metallation of the sulfamoyl pyrazole 15with n-butyllithium followed by direct halogenation of the anion witheither hexachloroethane (for R² being Cl) or1,2-dibromo-tetrachloroethane (for R² being Br) affords the halogenatedderivatives 16 (where R² is Cl or Br). Removal of the sulfamoyl groupwith trifluoroacetic acid (TFA) at room temperature proceeds cleanly andin good yield to afford the pyrazoles 12 wherein R² is Cl or Brrespectively.

As an alternative to the method illustrated in Scheme 13,pyrazolecarboxylic acids of Formula 5 wherein R² is CF₃ can also beprepared by the method outlined in Scheme 15. Reaction of a compound ofFormula 17 (wherein R⁸ is C₁-C₄ alkyl) with a suitable base in asuitable organic solvent affords the cyclized product of Formula 18after neutralization with an acid such as acetic acid.

The suitable base can be for example but not limited to, sodium hydride,potassium t-butoxide, dimsyl sodium (CH₃S(O)CH₂—Na⁺), alkali metal (suchas lithium, sodium or potassium) carbonates or hydroxides, tetraalkyl(such as methyl, ethyl or butyl)ammonium fluorides or hydroxides, or2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphonine.The suitable organic solvent can be, for example but not limited to,acetone, acetonitrile, tetrahydrofuran, dichloromethane,dimethylsulfoxide, or N,N-dimethylformamide. The cyclization reaction isusually conducted in a temperature range from about 0 to 120° C. Theeffects of solvent, base, temperature and addition time are allinterdependent, and choice of reaction conditions is important tominimize the formation of byproducts. A preferred base istetrabutylammonimm fluoride.

Dehydration of the compound of Formula 18 to give the compound ofFormula 19, followed by hydrolysis of the carboxylic ester function tocarboxylic acid, affords the compound of Formula 5. The dehydration isaccomplished by treatment with a catalytic amount of a suitable acid.This catalytic acid can be, for example but not limited to, sulfuricacid. The reaction is generally conducted using an organic solvent. Asone skilled in the art will realize, dehydration reactions may beconducted in a wide variety of solvents, e.g. acetic acid, in atemperature range generally between about 0 and 200° C., more preferablybetween about 0 and 100° C. Carboxylic esters of Formula 19 can beconverted to carboxylic acids of Formula 5 by numerous methods includingnucleophilic cleavage under anhydrous conditions or hydrolytic methodsinvolving the use of either acids or bases (see T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley &Sons, Inc., New York, 1991, pp. 224-269 for a review of methods). Forthe method of Scheme 15, base-catalyzed hydrolytic methods arepreferred. Suitable bases include alkali metal (such as lithium, sodiumor potassium) hydroxides. For example, the ester can be dissolved in amixture of water and an alcohol such as ethanol. Upon treatment withsodium hydroxide or potassium hydroxide, the ester is saponified toprovide the sodium or potassium salt of the carboxylic acid.Acidification with a strong acid, such as hydrochloric acid or sulfuricacid, yields the carboxylic acid of Formula 5.

Compounds of Formula 17 wherein R² is CF₃ can be prepared by the methodoutlined in Scheme 16. Treatment of a hydrazine compound of Formula 20with a ketone of Formula CH₃COR² in a solvent such as water, methanol oracetic acid gives the hydrazone of Formula 21.

One skilled in the art will recognize that this reaction may requirecatalysis by an optional acid and may also require elevated temperaturesdepending on the molecular substitution pattern of the hydrazone ofFormula 21. Reaction of the hydrazone of Formula 21 with an alkylchlorooxalate in a suitable organic solvent such as, for example but notlimited to, dichloromethane or tetrahydrofuran in the presence of anacid scavenger such as triethylamine provides the compound of Formula17. The reaction is usually conducted at a temperature between about 0and 100° C. Hydrazine compounds of Formula 20 can be prepared bystandard methods, such as by reaction of the corresponding halopyridineof Formula 13 with hydrazine.

As an alternative to the method illustrated in Scheme 13,pyrazolecarboxylic acids of Formula 5 wherein R² is Cl or Br can also beprepared by the method outlined in Scheme 17. Oxidation of the compoundof Formula 22, optionally in the presence of acid, gives the compound ofFormula 19, wherein R² is Cl or Br. Hydrolysis of the carboxylic esterfunction to the carboxylic acid provides the compound of Formula 5.

The oxidizing agent for converting a compound of Formula 22 to acompound of Formula 19 can be hydrogen peroxide, organic peroxides,potassium persulfate, sodium persulfate, ammonium persulfate, potassiummonopersulfate (e.g., Oxone®) or potassium permanganate. To obtaincomplete conversion, at least one equivalent of oxidizing agent versusthe compound of Formula 22 should be used, preferably between about oneto two equivalents. This oxidation is typically carried out in thepresence of a solvent. The solvent can be an ether, such astetrahydrofuran, p-dioxane and the like, an organic ester, such as ethylacetate, dimethyl carbonate and the like, or a polar aprotic organicsuch as N,N-dimethylformamide, acetonitrile and the like. Acids suitablefor use in the oxidation step include inorganic acids, such as sulfuricacid, phosphoric acid and the like, and organic acids, such as aceticacid, benzoic acid and the like. One to five equivalents of acid can beused. The preferred oxidant is potassium persulfate and the oxidation ispreferably carried out in the presence of sulfuric acid. The reactioncan be carried out by mixing the compound of Formula 22 in the desiredsolvent and, if used, the acid. The oxidant can then be added at aconvenient rate. The reaction temperature is typically varied from aslow as about 0° C. up to the boiling point of the solvent in order toobtain a reasonable reaction time to complete the reaction. Methodssuitable for converting the ester of Formula 19 to the carboxylic acidof Formula 5 are already described for Scheme 15.

Compounds of Formula 22, wherein R² is halogen and R⁸ is C₁-C₄ alkyl,can be prepared from the corresponding compounds of Formula 23 as shownin Scheme 18.

Treatment of a compound of Formula 23 with a halogenating reagent,usually in the presence of a solvent, affords the corresponding halocompound of Formula 22. Halogenating reagents that can be used includephosphorus oxyhalides, phosphorus trihalides, phosphorus pentahalides,thionyl chloride, dihalotrialkylphosphoranes,dihalodiphenylphosphoranes, oxalyl chloride and phosgene. Preferred arephosphorus oxyhalides and phosphorus pentahalides. To obtain completeconversion, at least 0.33 equivalents of phosphorus oxyhalide versus thecompound of Formula 23 should be used, preferably between about 0.33 and1.2 equivalents. To obtain complete conversion, at least 0.20equivalents of phosphorus pentahalide versus the compound of Formula 23should be used, preferably between about 0.20 and 1.0 equivalents.Typical solvents for this halogenation include halogenated alkanes, suchas dichloromethane, chloroform, chlorobutane and the like, aromaticsolvents, such as benzene, xylene, chlorobenzene and the like, ethers,such as tetrahydrofuran, p-dioxane, diethyl ether, and the like, andpolar aprotic solvents such as acetonitrile, N,N-dimethylformamide, andthe like. Optionally, an organic base, such as triethylamine, pyridine,N,N-dimethylaniline or the like, can be added. Addition of a catalyst,such as N,N-dimethylformamide, is also an option. Preferred is theprocess in which the solvent is acetonitrile and a base is absent.Typically, neither a base nor a catalyst is required when acetonitrilesolvent is used. The preferred process is conducted by mixing thecompound of Formula 23 in acetonitrile. The halogenating reagent is thenadded over a convenient time, and the mixture is then held at thedesired temperature until the reaction is complete. The reactiontemperature is typically between 20° C. and the boiling point ofacetonitrile, and the reaction time is typically less than 2 hours. Thereaction mass is then neutralized with an inorganic base, such as sodiumbicarbonate, sodium hydroxide and the like, or an organic base, such assodium acetate. The desired product of Formula 22 can be isolated bymethods known to those skilled in the art, including crystallization,extraction and distillation.

Alternatively, compounds of Formula 22 wherein. R² is Br or Cl can beprepared by treating the corresponding compounds of Formula 22 whereinR² is a different halogen (e.g., Cl for making Formula 22 wherein R² isBr) or a sulfonate group such as p-toluenesulfonate, benzenesulfonateand methanesulfonate with hydrogen bromide or hydrogen chloride,respectively. By this method the R² halogen or sulfonate substituent onthe compound of Formula 22 is replaced with Br or Cl from hydrogenbromide or hydrogen chloride, respectively. The reaction is conducted ina suitable solvent such as dibromomethane, dichloromethane, acetic acid,ethyl acetate or acetonitrile. The reaction can be conducted at or nearatmospheric pressure or above atmospheric pressure in a pressure vessel.The halogenating reagent can be added in the form of a gas to thereaction mixture containing the Formula 23 compound and solvent. When R²in the starting compound of Formula 22 is a halogen such as Cl, thereaction is preferably conducted in such a way that sparging or othersuitable means removes the hydrogen halide generated from the reaction.Alternatively, the halogenating reagent can first be dissolved in aninert solvent in which it is highly soluble (such as acetic acid) beforecontacting the compound of Formula 23 either neat or in solution. Thereaction can be conducted between about 0 and 100° C., most convenientlynear ambient temperature (e.g., about 10 to 40° C.), and more preferablybetween about 20 and 30° C. Addition of a Lewis acid catalyst (such asaluminum tribromide for preparing Formula 22 wherein R² is Br) canfacilitate the reaction. The product of Formula 22 is isolated by theusual methods known to those skilled in the art, including extraction,distillation and crystallization.

Starting compounds of Formula 22 wherein R² is a sulfonate group can beprepared from corresponding compounds of Formula 23 by standard methodssuch as treatment with a sulfonyl chloride (e.g., p-toluenesulfonylchloride) and base such as a tertiary amine (e.g., triethylamine) in asuitable solvent such as dichloromethane.

As an alternative to the method illustrated in Scheme 13,pyrazolecarboxylic acids of Formula 5 wherein R² is haloalkoxy can alsobe prepared by the method outlined in Scheme 19. A compound of Formula23 is oxidized to a compound of Formula 24. The reaction conditions forthis oxidation are as described for the conversion of the compound ofFormula 22 to the compound of Formula 19 in Scheme 17.

The intermediate of Formula 24 is then alkylated to form a compound ofFormula 19 (wherein R² is haloalkoxy) by reaction with an appropriatehaloalkylating agent such as a haloalkyl halide or sulfonate. Thereaction is conducted in the presence of at least one equivalent of abase. Suitable bases include inorganic bases, such as alkali metal (suchas lithium, sodium or potassium) carbonates, hydroxides and hydrides ororganic bases, such as triethylamine, diisopropylethylamine and1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is generally conductedin a solvent, which can comprise alcohols, such as methanol and ethanol,halogenated alkanes, such as dichloromethane, aromatic solvents, such asbenzene, toluene and chlorobenzene, ethers, such as tetrahydrofuran, andpolar aprotic solvents, such as such as acetonitrile,N,N-dimethylformamide, and the like. Alcohols and polar aprotic solventsare preferred for use with inorganic bases. Potassium carbonate as baseand N,N-dimethylformamide or acetonitrile as solvent are preferred. Thereaction is generally conducted between 0 and 150° C., most typicallybetween ambient temperature and 100° C. The ester of Formula 24 can thenbe converted to the carboxylic acid of Formula 5 by the methods alreadydescribed for the conversion of a compound of Formula 19 to a compoundof Formula 5 in Scheme 15.

Compounds of Formula 23 can be prepared from compounds of Formula 20 asoutlined in Scheme 20. In this method, a hydrazine compound of Formula20 is allowed to react with a compound of Formula 25 (a fumarate esteror maleate ester or a mixture thereof can be used) in the presence of abase and a solvent.

The base used in Scheme 20 is typically a metal alkoxide salt, such assodium methoxide, potassium methoxide, sodium ethoxide, potassiumethoxide, potassium tert-butoxide, lithium tert-butoxide, and the like.Polar protic and polar aprotic organic solvents can be used, such asalcohols, acetonitrile, tetrahydrofuran, N,N-dimethyl-formamide,dimethyl sulfoxide and the like. Preferred solvents are alcohols such asmethanol and ethanol. It is especially preferred that the alcohol be thesame as that making up the fumarate or maleate ester and the alkoxidebase. The reaction is typically conducted by mixing the compound ofFormula 20 and the base in the solvent. The mixture can be heated orcooled to a desired temperature and the compound of Formula 25 addedover a period of time. Typically reaction temperatures are between 0° C.and the boiling point of the solvent used. The reaction may be conductedunder greater than atmospheric pressure in order to increase the boilingpoint of the solvent. Temperatures between about 30 and 90° C. aregenerally preferred. The reaction can then be acidified by adding anorganic acid, such as acetic acid and the like, or an inorganic acid,such as hydrochloric acid, sulfuric acid and the like. The desiredproduct of Formula 23 can be isolated by methods known to those skilledin the art, such as crystallization, extraction or distillation.

It is recognized that some reagents and reaction conditions describedabove for preparing compounds of Formula 1 may not be compatible withcertain functionalities present in the intermediates. In theseinstances, the incorporation of protection/deprotection sequences orfunctional group interconversions into the synthesis will aid inobtaining the desired products. The use and choice of the protectinggroups will be apparent to one skilled in chemical synthesis (see, forexample, T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art willrecognize that, in some cases, after the introduction of a given reagentas it is depicted in any individual scheme, it may be necessary toperform additional routine synthetic steps not described in detail tocomplete the synthesis of compounds of Formula 1. One skilled in the artwill also recognize that it may be necessary to perform a combination ofthe steps illustrated in the above schemes in an order other than thatimplied by the particular sequence presented to prepare the compounds ofFormula 1.

Without further elaboration, it is believed that one skilled in the artusing the preceding description can utilize the present invention to itsfullest extent. The following Examples are, therefore, to be construedas merely illustrative, and not limiting of the disclosure in any waywhatsoever. Steps in the following Examples illustrate a procedure foreach step in an overall synthetic transformation, and the startingmaterial for each step may not have necessarily been prepared by aparticular preparative run whose procedure is described in otherExamples or Steps. Percentages are by weight except for chromatographicsolvent mixtures or where otherwise indicated. Parts and percentages forchromatographic solvent mixtures are by volume unless otherwiseindicated. ¹H NMR spectra are reported in ppm downfield fromtetramethylsilane; “s” means singlet, “d” means doublet, “t” meanstriplet, “q” means quartet, “m” means multiplet, “dd” means doublet ofdoublets, “dt” means doublet of triplets, and “br s” means broadsinglet.

Example 1 Preparation of1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-(aminocarbonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideStep A: Preparation of 2-amino-3-methyl-5-iodobenzoic acid

To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 5 g, 33 mmol) inN,N-dimethylformamide (30 mL) was added N-iodosuccinimide (7.8 g, 34.7mmol), and the reaction mixture was suspended in a 75° C. oil bathovernight. The heat was removed and the reaction mixture was then slowlypoured into ice-water (100 mL) to precipitate a light grey solid. Thesolid was filtered and washed four times with water and then placed in avacuum oven at 70° C. to dry overnight. The desired intermediate wasisolated as a light grey solid (8.8 g).

¹H NMR (DMSO-d₆): δ 7.86 (d, 1H), 7.44 (d, 1H), 2.08 (s, 3H).

Step B: Preparation of3-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine

To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and3-(trifluoromethyl)-pyrazole (83 g, 0.61 mol) in dryN,N-dimethylformamide (300 mL) was added potassium carbonate (166.0 g,1.2 mol) and the reaction was then heated to 110-125° C. over 48 hours.The reaction was cooled to 100° C. and filtered through Celite®diatomaceous filter aid to remove solids. N,N-Dimethylformamide andexcess dichloropyridine were removed by distillation at atmosphericpressure. Distillation of the product at reduced pressure (b.p. 139-141°C., 7 mm) afforded 113.4 g of the desired intermediate as a clear yellowoil.

¹H NMR (CDCl₃): δ 8.45 (d, 1H), 8.15 (s, 1H), 7.93 (d, 1H), 7.36 (t,1H), 6.78 (s, 1H).

Step C: Preparation of1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid

To a solution of3-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine (i.e. thepyrazole product from Step B) (105.0 g, 425 mmol) in dry tetrahydrofuran(700 ml) at −75° C. was added via cannula a −30° C. solution of lithiumdiisopropylamide (425 mmol) in dry tetrahydrofuran (300 mL). The deepred solution was stirred for 15 minutes, after which time carbon dioxidewas bubbled through at −63° C. until the solution became pale yellow andthe exothermicity ceased. The reaction was stirred for an additional 20minutes and then quenched with water (20 mL). The solvent was removedunder reduced pressure, and the reaction mixture partitioned betweenether and 0.5 N aqueous sodium hydroxide solution. The aqueous extractswere washed with ether (3×), filtered through Celite® diatomaceousfilter aid to remove residual solids, and then acidified to a pH ofapproximately 4, at which point an orange oil fainted. The aqueousmixture was stirred vigorously and additional acid was added to lowerthe pH to 2.5-3. The orange oil congealed into a granular solid, whichwas filtered, washed successively with water and 1 N hydrochloric acid,and dried under vacuum at 50° C. to afford 130 g of the title product asan off-white solid. Product from another run following a similarprocedure melted at 175-176° C.

¹H NMR (DMSO-d₆): δ 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60 (d,1H).

Step D: Preparation of2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one

To a solution of methanesulfonyl chloride (2.91 mL, 37.74 mmol) inacetonitrile (50 mL) was added dropwise a mixture of1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (i.e. the carboxylic acid product of Step C) (10.0 g, 34.31 mmol)and triethylamine (4.78 mL, 34.31 mmol) in acetonitrile (50 mL) at −5°C. The reaction temperature was then maintained at 0° C. throughoutsuccessive addition of reagents. After stirring for 20 minutes,2-amino-3-methyl-5-iodobenzoic acid (i.e. the product from Step A) (9.51g, 34.31 mmol) was added and stirring was continued for an additional 10minutes. A solution of triethylamine (9.56 mL, 68.62 mmol) inacetonitrile (15 mL) was then added dropwise, and the reaction mixturewas stirred 30 minutes, followed by the addition of methanesulfonylchloride (2.91 mL, 37.74 mmol). The reaction mixture was then warmed toroom temperature and stirred 2 hours. The solvent was evaporated underreduced pressure, and the residual solid was purified by chromatographyon silica gel to afford 8.53 g of the title compound as a yellow solid.

¹H NMR (CDCl₃): δ 8.59 (dd, 1H), 8.35 (d, 1H), 7.97 (dd, 1H), 7.86 (d,1H), 7.49 (m, 2H), 1.79 (s, 3H).

Step E: Preparation of2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one

To a solution of2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one(i.e. the benzoxazinone product of Step D) (500 mg, 0.94 mmol) intetrahydrofuran (10 mL) was added copper(I) iodide (180 mg, 0.094 mmol),tetrakis(triphenyphosphine)palladium(0) (5.4 mg, 0.047 mmol) andcopper(I) cyanide (420 mg, 4.7 mmol) sequentially at room temperature.After heating the reaction mixture at reflux overnight, additionalcopper(I) cyanide (420 mg, 4.7 mmol), copper(I) iodide (107 mg, 0.56mmol) and tetrakis(triphenylphosphine)palladium(0) (325 mg, 0.28 mmol)were added and the reflux was continued for 1 hour. The reaction mixtureturned black in color, at which point thin layer chromatography onsilica gel confirmed completion of the reaction. The reaction mixturewas then diluted with ethyl acetate (20 mL) and filtered throughCelite®, followed by washing three times with 10% aqueous sodiumbicarbonate solution and once with brine. The organic extract was dried(MgSO₄) and concentrated under reduced pressure to afford 410 mg of thetitle compound as a crude yellow solid.

¹H NMR (CDCl₃): δ 8.59 (dd, 1H), 8.33 (d, 1H), 8.03 (dd, 1H), 7.95 (d,1H), 7.56 (m, 2H), 1.88 (s, 3H).

Step F: Preparation of1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-(aminocarbonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one(i.e. the cyanobenzoxazinone product of Step E) (200 mg, 0.46 mmol) intetrahydrofuran (5 mL) was added dropwise ammonium hydroxide (0.5 mL,12.8 mmol) at room temperature. The reaction mixture was then stirredfor five minutes, at which point thin layer chromatography on silica gelconfirmed completion of the reaction. The tetrahydrofuran solvent wasevaporated under reduced pressure, and the residual solid was purifiedby chromatography on silica gel to afford 620 mg of the title compound,a compound of the present invention, as a solid melting at 200-202° C.

¹H NMR (CDCl₃): δ 10.65 (s, 1H), 8.43 (dd, 1H), 7.9 (dd, 1H), 7.67 (s,1H), 7.63 (s, 1H), 7.45 (m, 1H), 7.25 (s, 1H), 6.21 (bs, 1H), 5.75 (bs,1H), 2.26, (s, 3H).

Example 2 Preparation of1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideStep A: Preparation of1-(3-chloro-2-pyridinyl)-N-[4-iodo-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one(i.e. the benzoxazinone product of Example 1, Step D) (500 mg, 0.94mmol) in tetrahydrofuran (15 mL) was added dropwise methylamine (2.0 Msolution in THF, 1.4 mL, 2.8 mmol) and the reaction mixture was stirredfor 3 hours, at which point thin layer chromatography on silica: gelconfirmed completion of the reaction. The tetrahydrofuran solvent wasevaporated under reduced pressure and the residual solid was purified bychromatography on silica gel to afford 400 mg of the title compound as ayellow solid.

¹H NMR (CDCl₃): δ 10.25 (s, 1H), 8.45 (dd, 1H), 7.85 (dd, 1H), 7.55 (s,1H), 7.50 (s, 1H), 7.46 (s, 1H), 7.40 (m, 1H), 6.15 (d, 1H), 2.93 (d,3H), 2.12 (s, 3H).

Step B: Preparation of1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of1-(3-chloro-2-pyridinyl)-N-[4-iodo-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(i.e. the diamide product of Step A) (410 mg, 0.72 mmol) intetrahydrofuran (8 mL) was added copper(I) iodide (24 mg, 0.126 mmol),tetrakis(triphenyphosphine)palladium(0) (70 mg, 0.060 mmol) andcopper(I) cyanide (640 mg, 7.2 mmol) sequentially at room temperature.The reaction mixture was heated at reflux for 4.5 hours. Thin layerchromatography on silica gel confirmed completion of the reaction. Thereaction mixture was then diluted with ethyl acetate (20 mL) andfiltered through Celite®, followed by washing three times with 10%aqueous sodium bicarbonate solution and once with brine. The organicextract was dried (MgSO₄) and concentrated under reduced pressure andthe residual solid was purified by chromatography on silica gel toafford 114 mg of the title compound, a compound of the presentinvention, as a white solid, melting at 214-216° C.

¹H NMR (CDCl₃): δ 10.70 (s, 1H), 8.46 (dd, 1H), 7.87 (dd, 1H), 7.57 (s,2H), 7.45 (m, 1H), 7.31 (s, 1H), 6.35 (d, 1H), 2.98 (d, 3H), 2.24 (s,3H),

Example 3 Preparation of3-chloro-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamideStep A: Preparation of 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide

To a solution of N-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol) in drytetrahydrofuran (1500 mL) at −78° C. was added dropwise a solution of2.5 M n-butyl-lithium (472, mL, 1.18 mol) in hexane while maintainingthe temperature below −65° C. Upon completion of the addition thereaction mixture was maintained at −78° C. for an additional 45 minutes,after which time a solution of hexachloroethane (279 g, 1.18 mol) intetrahydrofuran (120 mL) was added dropwise. The reaction mixture wasmaintained for an hour at −78° C., warmed to −20° C. and then quenchedwith water (1 L). The reaction mixture was extracted with methylenechloride (4×500 mL); the organic extracts were dried over magnesiumsulfate and concentrated. The crude product was further purified bychromatography on silica gel using methylene chloride as eluent toafford 160 g of the title product compound as a yellow oil.

¹H NMR (CDCl₃): δ 7.61 (s, 1H), 6.33 (s, 1H), 3.07 (d, 6H).

Step B: Preparation of 3-chloropyrazole

To trifluoroacetic acid (290 mL) was added dropwise3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (i.e. the chloropyrazoleproduct of Step A) (160 g), and the reaction mixture was stirred at roomtemperature for 1.5 hrs and then concentrated at reduced pressure. Theresidue was taken up in hexane, insoluble solids were filtered off, andthe hexane was concentrated to afford the crude product as an oil. Thecrude product was further purified by chromatography on silica gel usingether/hexane (40:60) as eluent to afford 64.44 g of the title product asa yellow oil.

¹H NMR (CDCl₃): δ 6.39 (s, 1H), 7.66 (s, 1H), 9.6 (br s, 1H).

Step C: Preparation of 3-chloro-2-(3-chloro-1H-pyrazol-1-yl)pyridine

To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and3-chloropyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) inN,N-dimethylformamide (400 mL) was added potassium carbonate (147.78 g,1.06 mol), and the reaction mixture was then heated to 100° C. for 36hours. The reaction mixture was cooled to room temperature and slowlypoured into ice water. The precipitated solids were filtered and washedwith water. The solid filter cake was taken up in ethyl acetate, driedover magnesium sulfate and concentrated. The crude solid waschromatographed on silica gel using 20% ethyl acetate/hexane as eluentto afford 39.75 g of the title product as a white solid.

¹H NMR (CDCl₃): δ 6.43 (s, 1H), 7.26 (m, 1H), 7.90 (d, 1H), 8.09 (s,1H), 8.41 (d, 1H).

Step D: Preparation of3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

To a solution of 3-chloro-2-(3-chloro-1H-pyrazol-1-yl)pyridine (i.e. thepyrazole product of Step C) (39.75 g, 186 mmol) in dry tetrahydrofuran(400 mL) at −78° C. was added dropwise a solution of 2.0 Mdiisopropylamide (93 mL, 186 mmol) in tetrahydrofuran. Carbon dioxidewas bubbled through the amber solution for 1.4 minutes, after which timethe solution became pale brownish-yellow. The reaction was made basicwith 1 N aqueous sodium hydroxide solution and extracted with ether(2×500 mL). The aqueous extracts were acidified with 6 N hydrochloricacid followed by extraction with ethyl acetate (3×500 mL). The ethylacetate extracts were dried over magnesium sulfate and concentrated toafford 42.96 g of the title product as an off-white solid. Product fromanother run following the same procedure melted at 198-199° C.

¹H NMR (DMSO-d₆): δ 6.99 (s, 1H), 7.45 (m, 1H), 7.93 (d, 1H), 8.51 (d,1H).

Step E: Preparation of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one

To a solution of methanesulfonyl chloride (0.63 mL, 8.13 mmol) inacetonitrile (10 mL) was added dropwise a mixture of3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e.the carboxylic acid product of Step D) (2.0 g, 7.75 mmol) andtriethylamine (1.08 ml, 7.75 mmol) in acetonitrile (5 mL) at 0° C. Thereaction mixture was then stirred for 15 minutes at 0° C. Then,2-amino-3-methyl-5-iodobenzoic acid (i.e. the product from Example 1,Step A) (2.14 g, 7.75 mmol) was added, and stirring was continued for anadditional 5 minutes. A solution of triethylamine (2.17 mL, 15.15 mmol)in acetonitrile (5 mL) was then added dropwise while keeping thetemperature below 5° C. The reaction mixture was stirred 40 minutes at0° C., and then methanesulfonyl chloride (0.63 mL, 8.13 mmol) was added.The reaction mixture was then warmed to room temperature and stirredovernight. The reaction mixture was then diluted with water (50 mL), andextracted with ethyl acetate (3×50 mL). The combined ethyl acetateextracts were washed successively with 10% aqueous sodium bicarbonate(1×20 mL) and brine (1×20 mL), dried (MgSO₄) and concentrated to afford3.18 g of the title product as a crude yellow solid.

¹H NMR (CDCl₃): δ 8.55 (dd, 1H), 8.33 (s, 1H), 7.95 (dd, 1H), 7.82 (d,1H), 7.45 (m, 1H), 7.16 (s, 1H), 1.77 (s, 3H).

Step F: Preparation of2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one

To a solution of2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one(i.e. the benzoxazinone product of Step E) (600 mg; 1.2 mmol) intetrahydrofuran (15 mL) was added copper(I) iodide (137 mg, 0.72 mmol),tetrakis(triphenyphosphine)palladium(0) (416 mg, 0.36 mmol) andcopper(I) cyanide (860 mg, 9.6 mmol) sequentially at room temperature.The reaction mixture was then heated at reflux overnight. The reactionturned black in color, at which point thin layer chromatography onsilica gel confirmed completion of the reaction. The reaction wasdiluted with ethyl acetate (20 mL) and filtered through Celite®,followed by washing three times with 10% aqueous sodium bicarbonatesolution and once with brine. The organic extract was dried (MgSO₄) andconcentrated under reduced pressure to afford 397 mg of the titlecompound as a crude yellow solid.

¹H NMR (CDCl₃): δ 8.50 (q, 1H), 8.22 (d, 1H), 7.90 (dd, 1H), 7.67 (d,1H), 7.45 (m, 1H), 7.15 (s, 1H), 1.79 (s, 3H).

Step G: Preparation of3-chloro-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide

To a solution of2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one(e.g. the cyanobenzoxazinone product of Step F) (100 mg, 0.25 mmol) intetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution inMT, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5minutes, at which point thin layer chromatography on silica gelconfirmed completion of the reaction. The tetrahydrofuran solvent wasevaporated under reduced pressure, and the residual solid was purifiedby chromatography on silica gel to afford the title compound, a compoundof the present invention, as a white solid (52 mg), which decomposed inthe melting apparatus above 140° C.

¹H NMR (CDCl₃): δ 10.55 (s, 1H), 8.45 (dd, 1H), 7.85 (dd, 1H), 7.55 (d,2H), 7.40 (m, 1H), 6.97 (d, 1H), 6.30 (d, 1H), 2.98 (d, 3H), 2.24 (d,3H).

Example 4 Preparation of3-chloro-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-(aminocarbonyl)phenyl]-1H-pyrazole-5-carboxamide

To a solution of2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one(i.e. the cyano-benzoxazinone product of Example 3, Step F) (100 mg,0.25 mmol) tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide(0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was thenstirred for five minutes, at which point thin layer chromatography onsilica gel confirmed completion of the reaction. The tetrahydrofuransolvent was evaporated under reduced pressure, and the residual solidwas purified by chromatography on silica gel to afford 55 mg of thetitle compound, a compound of the present invention, as a white solidthat decomposes in the melting apparatus above 255° C.

¹H NMR (CDCl₃): δ 10.50 (s, 1H), 8.45 (dd, 1H), 7.85 (dd, 1H), 7.66 (d,1H), 7.61 (s, 1H), 7.41 (m, 1H), 6.95 (s, 1H), 6.25 (bs, 1H), 5.75 (bs,1H), 2.52 (s, 3H).

Example 5 Preparation of3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamideStep A: Preparation of 3-bromo-N,N-dimethyl-1H-pyrazole-1-sulfonamide

To a solution of N,N-dimethylsulfamoylpyrazole (44.0 g, 0.251 mol) indry tetrahydrofuran (500 mL) at −78° C. was added dropwise a solution ofn-butyllithium (2.5 M in hexane, 105.5 mL, 0.264 mol) while maintainingthe temperature below −60° C. A thick solid formed during the addition.Upon completion of the addition the reaction mixture was maintained foran additional 15 minutes, after which time a solution of1,2-dibromo-tetrachloroethane (90 g, 0.276 mol) in tetrahydrofuran (150mL) was added dropwise while maintaining the temperature below −70° C.The reaction mixture turned a clear orange; stirring was continued foran additional 15 minutes. The −78° C. bath was removed and the reactionwas quenched with water (600 mL). The reaction mixture was extractedwith methylene chloride (4×), and the organic extracts were dried overmagnesium sulfate and concentrated. The crude product was furtherpurified by chromatography on silica gel using methylene chloride-hexane(50:50) as eluent to afford 57.04 g of the title product as clearcolorless oil.

¹H NMR (CDCl₃): δ 3.07 (d, 6H), 6.44 (m, 1H), 7.62 (m, 1H).

Step B: Preparation of 3-bromopyrazole

To trifluoroacetic acid (70 mL) was slowly added3-bromo-N,N-dimethyl-1H-pyrazole-1-sulfonamide (i.e. the bromopyrazoleproduct of Step A) (57.04 g). The reaction mixture was stirred at roomtemperature for 30 minutes and then concentrated at reduced pressure.The residue was taken up in hexane, insoluble solids were filtered off,and the hexane was evaporated to afford the crude product as an oil. Thecrude product was further purified by chromatography on silica gel usingethyl acetate/dichloromethane (10:90) as eluent to afford an oil. Theoil was taken up in dichloromethane, neutralized with aqueous sodiumbicarbonate solution, extracted with methylene chloride (3×), dried overmagnesium sulfate and concentrated to afford 25.9 g of the title productas a white solid, m.p. 61-64° C.

¹H NMR (CDCl₃): δ 6.37 (d, 1H), 7.59 (d, 1H), 12.4 (br s, 1H).

Step C: Preparation of 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine

To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dryN,N-dimethylformamide (88 mL) was added potassium carbonate (48.6 g, 352mmol), and the reaction mixture was heated to 125° C. for 18 hours. Thereaction mixture was cooled to room temperature and poured into icewater (800 mL). A precipitate formed. The precipitated solids werestirred for 1.5 h, filtered and washed with water (2×100 mL). The solidfilter cake was taken up in methylene chloride and washed sequentiallywith water, 1N hydrochloric acid, saturated aqueous sodium bicarbonatesolution, and brine. The organic extracts were then dried over magnesiumsulfate and concentrated to afford 39.9 g of a pink solid. The crudesolid was suspended in hexane and stirred vigorously for 1 hr. Thesolids were filtered, washed with hexane and dried to afford the titleproduct as an off-white powder (30.4 g) determined to be >94% pure byNMR. This material was used without further purification in Step D.

¹H NMR (CDCl₃): δ 6.52 (s, 1H), 7.30 (dd, 1H), 7.92 (d, 1H), 8.05 (s,1H), 8.43 (d, 1H).

Step D: Preparation of3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

To a solution of 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine (i.e. thepyrazole product of Step C) (30.4 g, 118 mmol) in dry tetrahydrofuran(250 mL) at −76° C. was added dropwise a solution of lithiumdiisopropylamide (118 mmol) in tetrahydrofuran at such a rate as tomaintain the temperature below −71° C. The reaction mixture was stirredfor 15 minutes at −76° C., and carbon dioxide was then bubbled throughfor 10 minutes, causing warming to −57° C. The reaction mixture waswarmed to −20° C. and quenched with water. The reaction mixture wasconcentrated and then taken up in water (1 L) and ether (500 mL), andthen aqueous sodium hydroxide solution (1 N, 20 mL) was added. Theaqueous extracts were washed with ether and acidified with hydrochloricacid. The precipitated solids were filtered, washed with water and driedto afford 27.7 g of the title product as a tan solid. Product fromanother run following similar procedure melted at 200-201° C.

¹H NMR (DMSO-d₆): δ 7.25 (s, 1H), 7.68 (dd, 1H), 8.24 (d, 1H), 8.56 (d,1H).

Step E: Preparation of2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one

To a solution of methanesulfonyl chloride (0.54 ml, 6.94 mmol) inacetonitrile (15 mL) was added dropwise a mixture of3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. thecarboxylic acid product of Step D) (2.0 g, 6.6 mmol) and triethylamine(0.92 ml, 6.6 mmol) in acetonitrile (5 mL) at 0° C. The reaction mixturewas then stirred for 15 minutes at 0° C. Then,2-amino-3-methyl-5-iodobenzoic acid (i.e. the product from Example 1,Step A) (1.8 g, 6.6 mmol) was added, and stirring was continued for anadditional 5 minutes. A solution of triethylamine (1.85 mL, 13.2 mmol)in acetonitrile (5 mL) was then added dropwise while keeping thetemperature below 5° C. The reaction mixture was stirred. 40 minutes at0° C., and then methanesulfonyl chloride (0.54 ml, 6.94 mmol) was added.The reaction mixture was then warmed to room temperature and stirredovernight. The reaction mixture was then diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined ethyl acetateextracts were washed successively with 10% aqueous sodium bicarbonate(1×20 ml) and brine (1×20 mL), dried (MgSO₄) and concentrated to afford2.24 g of the title product as a crude yellow solid.

¹H NMR (CDCl₃): δ 8.55 (dd, 1H), 8.33 (d, 1H), 7.95 (dd, 1H), 7.85 (s,1H), 7.45 (m, 1H), 7.25 (s, 1H), 1.77 (s, 3H).

Step F: Preparation of2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one

To a solution of2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one(i.e. the benzoxazinone product of Step E) (600 mg, 1.1 mmol) intetrahydrofuran (15 mL) was added copper(I) iodide (126 mg, 0.66 mmol),tetrakis(triphenyphosphine)palladium(0) (382 mg, 0.33 mmol) andcopper(I) cyanide (800 mg, 8.8 mmol) sequentially at room temperature.The reaction mixture was then heated at reflux overnight. The reactionturned black in color, at which point thin layer chromatography onsilica gel confirmed completion of the reaction. The reaction mixturewas diluted with ethyl acetate (20 mL) and filtered through Celite®,followed by washing three times with 10% sodium bicarbonate solution andonce with brine. The organic extract was dried (MgSO₄) and concentratedunder reduced pressure to afford 440 mg of the title compound as a crudeyellow solid.

¹H NMR (CDCl₃): δ 8.55 (m, 1H), 8.3.1 (d, 1H), 7.96 (dd, 1H), 7.73 (s,1H), 7.51 (m, 1H), 7.31 (s, 1H), 1.86 (s, 3H).

Step G: Preparation of3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide

To a solution of2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one(i.e. the cyanobenzoxazinone product of Step F) (100 mg, 0.22 mmol) intetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution inTHF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5minutes, at which point thin layer chromatography on silica gelconfirmed completion of the reaction. The tetrahydrofuran solvent wasevaporated under reduced pressure, and the residual solid was purifiedby chromatography on silica gel to afford the title compound, a compoundof the present invention, as a white solid (41 mg), which decomposed inthe melting apparatus above 180° C.

¹H NMR (CDCl₃): δ 10.55 (s, 1H), 8.45 (dd, 1H), 7.85 (dd, 1H), 7.57 (s,2H), 7.37 (m, 1H), 7.05 (s, 1H), 6.30 (d, 1H), 2.98 (d, 3H), 2.24 (s,3H).

Example 6 Preparation of3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-(aminocarbonyl)phenyl]-1H-pyrazole-5-carboxamide

To a solution of2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one(i.e. the cyanobenzoxazinone product of Example 5, Step F) (100 mg, 0.22mmol) in tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide(0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was thenstirred for five minutes, at which point thin layer chromatography onsilica gel confirmed completion of the reaction. The tetrahydrofuransolvent was evaporated under reduced pressure, and the residual solidwas purified by chromatography on silica gel to afford the titlecompound, a compound of the present invention, as a white solid (36 mg),with a melting point above 255° C.

¹H NMR (CDCl₃): δ10.52 (s, 1H), 8.45 (dd, 1H), 7.85 (dd, 1H), 7.65 (s,1H), 7.60 (s, 1H), 7.40 (m, 1H), 7.05 (s, 1H), 6.20 (bs, 1H), 5.75 (bs,1H), 2.25 (s, 3H).

Example 7 Preparation of3-chloro-1-(3-chloro-2-pyridinyl)-N-[2-chloro-4-cyano-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamideStep A: Preparation of 2-amino-3-chloro-5-iodobenzoic acid

To a solution of 2-amino-3-chlorobenzoic acid (Aldrich, 5 g, 29.1 mmol)in N,N-dimethylformamide (30 mL) was added N-iodosuccinimide (5.8 g, 26mmol) and the reaction mixture was heated at 60° C. overnight. The heatwas removed and the reaction mixture was then slowly poured intoice-water (100 mL) to precipitate a light brown solid. The solid wasfiltered and washed four times with water and then placed in a vacuumoven at 70° C. to dry overnight. The desired intermediate was isolatedas a light brown solid (7.2 g).

¹H NMR (DMSO-d): δ 7.96 (d, 1H), 7.76 (t, 1H).

Step B: Preparation of8-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-4H-3,1-benzoxazin-4-one

To a solution of methanesulfonyl chloride (0.31 mL, 4.07 mmol) inacetonitrile (10 mL) was added dropwise a mixture of3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e.the carboxylic acid product of Example 3, Step D) (1.0 g, 3.87 mmol) andtriethylamine (0.54 mL, 3.87 mmol) in acetonitrile (5 mL) at 0° C. Thereaction mixture was then stirred for 15 minutes at 0° C. Then,2-amino-3-chloro-5-iodobenzoic acid (i.e. the product from Step A) (1.15g, 3.87 mmol) was added, and stirring was continued for an additional 5minutes. A solution of triethylamine (1.08 mL, 7.74 mmol) inacetonitrile (5 mL) was then added dropwise while keeping thetemperature below 5° C. The reaction mixture was stirred 40 minutes at0° C., and then methanesulfonyl chloride (0.31 mL, 4.07 mmol) was added.The reaction mixture was then warmed to room temperature and stirredovernight. The reaction mixture was then diluted with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined ethyl acetateextracts were washed successively with 10% aqueous sodium bicarbonate(1×20 mL) and brine (1×20 mL), dried (MgSO₄) and concentrated underreduced pressure. The residual solid was purified by chromatography onsilica gel to afford 575 mg of the title compound as a crude yellowsolid.

¹H NMR (CDCl₃): δ 8.55 (q, 1H), 8.39 (d, 1H), 8.04 (d, 1H), 7.94 (dd,1H), 7.45 (m, 1H), 7.19 (s, 1H).

Step C: Preparation of8-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-4H-3,1-benzoxazin-4-one

To a solution of8-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-4H-3,1-benzoxazin-4-one(i.e. the benzoxazinone product of Step B) (575 mg, 1.1 mmol) intetrahydrofuran (15 mL) was added copper(I) iodide (840 mg, 0.44 mmol),tetrakis(triphenyphosphine)palladium(0) (255 mg, 0.22 mmol) andcopper(I) cyanide (500 mg, 5.5 mmol) sequentially at room temperature.The reaction mixture was then heated at reflux overnight. The reactionturned black in color, at which point thin layer chromatography onsilica gel confirmed completion of the reaction. The reaction wasdiluted with ethyl acetate (20 mL) and filtered through Celite®,followed by washing three times with 10% aqueous sodium bicarbonatesolution and once with brine. The organic extract was dried (MgSO₄) andconcentrated under reduced pressure to afford 375 mg of the titlecompound as a crude yellow solid.

¹H NMR (CDCl₃): δ 8.55 (q, 1H), 8.36 (d, 1H), 7.95 (m, 2H), 7.5 (m, 1H).

Step D: Preparation of3-chloro-1-(3-chloro-2-pyridinyl)-N-[2-chloro-4-cyano-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide

To a solution of8-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-4H-3,1-benzoxazin-4-one(i.e. the cyanobenzoxazinone product of Step C) (187 mg, 0.446 mmol) intetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution inTHF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5minutes, at which point thin layer chromatography on silica gelconfirmed completion of the reaction. The tetrahydrofuran solvent wasevaporated under reduced pressure, and the residual solid was purifiedby chromatography on silica gel to afford 49 mg of the title compound, acompound of the present invention, as a white solid that melted at197-200° C.

¹H NMR (CDCl₃): δ 10.05 (bs, 1H), 8.45 (q, 1H), 7.85 (dd, 1H), 7.70 (d,1H), 7.59 (d, 1H), 7.38 (m, 1H), 7.02 (s, 1H), 6.35 (d, 1H), 2.94 (d,3H).

By the procedures described herein together with methods known in theart, the following compounds of Table 1 can be prepared. The followingabbreviations are used in the Tables which follow: t means tertiary, smeans secondary, n means natural, i means iso, Me means methyl, Et meansethyl, Pr means propyl, i-Pr means isopropyl, Bu means butyl and CN iscyano.

TABLE 1 1

R¹ R² R³ R⁴ R⁵ Me Cl F H H Me Cl F Me H Me Cl F Et H Me Cl F i-Pr H MeCl F t-Bu H Me Cl F CH₂CN H Me Cl F CH(Me)CH₂SMe H Me Cl F C(Me)₂CH₂SMeH Me Cl F Me Me Me Cl Cl H H Me Cl Cl Me H Me Cl Cl Et H Me Cl Cl i-Pr HMe Cl Cl t-Bu H Me Cl Cl CH₂CN H Me Cl Cl CH(Me)CH₂SMe H Me Cl ClC(Me)₂CH₂SMe H Me Cl Cl Me Me Me Cl Br H H Me Cl Br Me H Me Cl Br Et HMe Cl Br i-Pr H Me Cl Br t-Bu H Me Cl Br CH₂CN H Me Cl Br CH(Me)CH₂SMe HMe Cl Br C(Me)₂CH₂SMe H Me Cl Br Me Me Me Br F H H Me Br F Me H Me Br FEt H Me Br F i-Pr H Me Br F t-Bu H Me Br F CH₂CN H Me Br F CH(Me)CH₂SMeH Me Br F C(Me)₂CH₂SMe H Me Br F Me Me Me Br Cl H H Me Br Cl Me H Me BrCl Et H Me Br Cl i-Pr H Me Br Cl t-Bu H Me Br Cl CH₂CN H Me Br ClCH(Me)CH₂SMe H Me Br Cl C(Me)₂CH₂SMe H Me Br Cl Me Me Me Br Br H H Me BrBr Me H Me Br Br Et H Me Br Br i-Pr H Me Br Br t-Bu H Me Br Br CH₂CN HMe Br Br CH(Me)CH₂SMe H Me Br Br C(Me)₂CH₂SMe H Me Br Br Me Me Me CF₃ FH H Me CF₃ F Me H Me CF₃ F Et H Me CF₃ F i-Pr H Me CF₃ F t-Bu H Me CF₃ FCH₂CN H Me CF₃ F CH(Me)CH₂SMe H Me CF₃ F C(Me)₂CH₂SMe H Me CF₃ F Me MeMe CF₃ Cl H H Me CF₃ Cl Me H Me CF₃ Cl Et H Me CF₃ Cl i-Pr H Me CF₃ Clt-Bu H Me CF₃ Cl CH₂CN H Me CF₃ Cl CH(Me)CH₂SMe H Me CF₃ Cl C(Me)₂CH₂SMeH Me CF₃ Cl Me Me Me CF₃ Br H H Me CF₃ Br Me H Me CF₃ Br Et H Me CF₃ Bri-Pr H Me CF₃ Br t-Bu H Me CF₃ Br CH₂CN H Me CF₃ Br CH(Me)CH₂SMe H MeCF₃ Br C(Me)₂CH₂SMe H Me CF₃ Br Me Me Me OCF₂H F H H Me OCF₂H F Me H MeOCF₂H F Et H Me OCF₂H F i-Pr H Me OCF₂H F t-Bu H Me OCF₂H F CH₂CN H MeOCF₂H F CH(Me)CH₂SMe H Me OCF₂H F C(Me)₂CH₂SMe H Me OCF₂H F Me Me MeOCF₂H Cl H H Me OCF₂H Cl Me H Me OCF₂H Cl Et H Me OCF₂H Cl i-Pr H MeOCF₂H Cl t-Bu H Me OCF₂H Cl CH₂CN H Me OCF₂H Cl CH(Me)CH₂SMe H Me OCF₂HCl C(Me)₂CH₂SMe H Me OCF₂H Cl Me Me Me OCF₂H Br H H Me OCF₂H Br Me H MeOCF₂H Br Et H Me OCF₂H Br i-Pr H Me OCF₂H Br t-Bu H Me OCF₂H Br CH₂CN HMe OCF₂H Br CH(Me)CH₂SMe H Me OCF₂H Br C(Me)₂CH₂SMe H Me OCF₂H Br Me MeMe OCH₂CF₃ F H H Me OCH₂CF₃ F Me H Me OCH₂CF₃ F Et H Me OCH₂CF₃ F i-Pr HMe OCH₂CF₃ F t-Bu H Me OCH₂CF₃ F CH₂CN H Me OCH₂CF₃ F CH(Me)CH₂SMe H MeOCH₂CF₃ F C(Me)₂CH₂SMe H Me OCH₂CF₃ F Me Me Me OCH₂CF₃ Cl H H Me OCH₂CF₃Cl Me H Me OCH₂CF₃ Cl Et H Me OCH₂CF₃ Cl i-Pr H Me OCH₂CF₃ Cl t-Bu H MeOCH₂CF₃ Cl CH₂CN H Me OCH₂CF₃ Cl CH(Me)CH₂SMe H Me OCH₂CF₃ ClC(Me)₂CH₂SMe H Me OCH₂CF₃ Cl Me Me Me OCH₂CF₃ Br H H Me OCH₂CF₃ Br Me HMe OCH₂CF₃ Br Et H Me OCH₂CF₃ Br i-Pr H Me OCH₂CF₃ Br t-Bu H Me OCH₂CF₃Br CH₂CN H Me OCH₂CF₃ Br CH(Me)CH₂SMe H Me OCH₂CF₃ Br C(Me)₂CH₂SMe H MeOCH₂CF₃ Br Me Me Me OCF₃ F H H Me OCF₃ F Me H Me OCF₃ F Et H Me OCF₃ Fi-Pr H Me OCF₃ F t-Bu H Me OCF₃ F CH₂CN H Me OCF₃ F CH(Me)CH₂SMe H MeOCF₃ F C(Me)₂CH₂SMe H Me OCF₃ F Me Me Me OCF₃ Cl H H Me OCF₃ Cl Me H MeOCF₃ Cl Et H Me OCF₃ Cl i-Pr H Me OCF₃ Cl t-Bu H Me OCF₃ Cl CH₂CN H MeOCF₃ Cl CH(Me)CH₂SMe H Me OCF₃ Cl C(Me)₂CH₂SMe H Me OCF₃ Cl Me Me MeOCF₃ Br H H Me OCF₃ Br Me H Me OCF₃ Br Et H Me OCF₃ Br i-Pr H Me OCF₃ Brt-Bu H Me OCF₃ Br CH₂CN H Me OCF₃ Br CH(Me)CH₂SMe H Me OCF₃ BrC(Me)₂CH₂SMe H Me OCF₃ Br Me Me Cl Cl F H H Cl Cl F Me H Cl Cl F Et H ClCl F i-Pr H Cl Cl F t-Bu H Cl Cl F CH₂CN H Cl Cl F CH(Me)CH₂SMe H Cl ClF C(Me)₂CH₂SMe H Cl Cl F Me Me Cl Cl Cl H H Cl Cl Cl Me H Cl Cl Cl Et HCl Cl Cl i-Pr H Cl Cl Cl t-Bu H Cl Cl Cl CH₂CN H Cl Cl Cl CH(Me)CH₂SMe HCl Cl Cl C(Me)₂CH₂SMe H Cl Cl Cl Me Me Cl Cl Br H H Cl Cl Br Me H Cl ClBr Et H Cl Cl Br i-Pr H Cl Cl Br t-Bu H Cl Cl Br CH₂CN H Cl Cl BrCH(Me)CH₂SMe H Cl Cl Br C(Me)₂CH₂SMe H Cl Cl Br Me Me Cl Br F H H Cl BrF Me H Cl Br F Et H Cl Br F i-Pr H Cl Br F t-Bu H Cl Br F CH₂CN H Cl BrF CH(Me)CH₂SMe H Cl Br F C(Me)₂CH₂SMe H Cl Br F Me Me Cl Br Cl H H Cl BrCl Me H Cl Br Cl Et H Cl Br Cl i-Pr H Cl Br Cl t-Bu H Cl Br Cl CH₂CN HCl Br Cl CH(Me)CH₂SMe H Cl Br Cl C(Me)₂CH₂SMe H Cl Br Cl Me Me Cl Br BrH H Cl Br Br Me H Cl Br Br Et H Cl Br Br i-Pr H Cl Br Br t-Bu H Cl Br BrCH₂CN H Cl Br Br CH(Me)CH₂SMe H Cl Br Br C(Me)₂CH₂SMe H Cl Br Br Me MeCl CF₃ F H H Cl CF₃ F Me H Cl CF₃ F Et H Cl CF₃ F i-Pr H Cl CF₃ F t-Bu HCl CF₃ F CH₂CN H Cl CF₃ F CH(Me)CH₂SMe H Cl CF₃ F C(Me)₂CH₂SMe H Cl CF₃F Me Me Cl CF₃ Cl H H Cl CF₃ Cl Me H Cl CF₃ Cl Et H Cl CF₃ Cl i-Pr H ClCF₃ Cl t-Bu H Cl CF₃ Cl CH₂CN H Cl CF₃ Cl CH(Me)CH₂SMe H Cl CF₃ ClC(Me)₂CH₂SMe H Cl CF₃ Cl Me Me Cl CF₃ Br H H Cl CF₃ Br Me H Cl CF₃ Br EtH Cl CF₃ Br i-Pr H Cl CF₃ Br t-Bu H Cl CF₃ Br CH₂CN H Cl CF₃ BrCH(Me)CH₂SMe H Cl CF₃ Br C(Me)₂CH₂SMe H Cl CF₃ Br Me Me Cl OCF₂H F H HCl OCF₂H F Me H Cl OCF₂H F Et H Cl OCF₂H F i-Pr H Cl OCF₂H F t-Bu H ClOCF₂H F CH₂CN H Cl OCF₂H F CH(Me)CH₂SMe H Cl OCF₂H F C(Me)₂CH₂SMe H ClOCF₂H F Me Me Cl OCF₂H Cl H H Cl OCF₂H Cl Me H Cl OCF₂H Cl Et H Cl OCF₂HCl i-Pr H Cl OCF₂H Cl t-Bu H Cl OCF₂H Cl CH₂CN H Cl OCF₂H ClCH(Me)CH₂SMe H Cl OCF₂H Cl C(Me)₂CH₂SMe H Cl OCF₂H Cl Me Me Cl OCF₂H BrH H Cl OCF₂H Br Me H Cl OCF₂H Br Et H Cl OCF₂H Br i-Pr H Cl OCF₂H Brt-Bu H Cl OCF₂H Br CH₂CN H Cl OCF₂H Br CH(Me)CH₂SMe H Cl OCF₂H BrC(Me)₂CH₂SMe H Cl OCF₂H Br Me Me Cl OCH₂CF₃ F H H Cl OCH₂CF₃ F Me H ClOCH₂CF₃ F Et H Cl OCH₂CF₃ F i-Pr H Cl OCH₂CF₃ F t-Bu H Cl OCH₂CF₃ FCH₂CN H Cl OCH₂CF₃ F CH(Me)CH₂SMe H Cl OCH₂CF₃ F C(Me)CH₂SMe H ClOCH₂CF₃ F Me Me Cl OCH₂CF₃ Cl H H Cl OCH₂CF₃ Cl Me H Cl OCH₂CF₃ Cl Et HCl OCH₂CF₃ Cl i-Pr H Cl OCH₂CF₃ Cl t-Bu H Cl OCH₂CF₃ Cl CH₂CN H ClOCH₂CF₃ Cl CH(Me)CH₂SMe H Cl OCH₂CF₃ Cl C(Me)₂CH₂SMe H Cl OCH₂CF₃ Cl MeMe Cl OCH₂CF₃ Br H H Cl OCH₂CF₃ Br Me H Cl OCH₂CF₃ Br Et H Cl OCH₂CF₃ Bri-Pr H Cl OCH₂CF₃ Br t-Bu H Cl OCH₂CF₃ Br CH₂CN H Cl OCH₂CF₃ BrCH(Me)CH₂SMe H Cl OCH₂CF₃ Br C(Me)₂CH₂SMe H Cl OCH₂CF₃ Br Me Me Cl OCF₃F H H Cl OCF₃ F Me H Cl OCF₃ F Et H Cl OCF₃ F i-Pr H Cl OCF₃ F t-Bu H ClOCF₃ F CH₂CN H Cl OCF₃ F CH(Me)CH₂SMe H Cl OCF₃ F C(Me)₂CH₂SMe H Cl OCF₃F Me Me Cl OCF₃ Cl H H Cl OCF₃ Cl Me H Cl OCF₃ Cl Et H Cl OCF₃ Cl i-Pr HCl OCF₃ Cl t-Bu H Cl OCF₃ Cl CH₂CN H Cl OCF₃ Cl CH(Me)CH₂SMe H Cl OCF₃Cl C(Me)₂CH₂SMe H Cl OCF₃ Cl Me Me Cl OCF₃ Br H H Cl OCF₃ Br Me H ClOCF₃ Br Et H Cl OCF₃ Br i-Pr H Cl OCF₃ Br t-Bu H Cl OCF₃ Br CH₂CN H ClOCF₃ Br CH(Me)CH₂SMe H Cl OCF₃ Br C(Me)₂CH₂SMe H Cl OCF₃ Br Me Me

TABLE 2

R¹ R² R³ R⁴ R⁶ R¹ R² R³ R⁴ R⁶ Me CF₃ Cl Me F Me CF₃ Cl Me Cl Cl CF₃ ClMe F Cl CF₃ Cl Me Cl Br CF₃ Cl Me F Br CF₃ Cl Me Cl Me Cl Cl Me F Me ClCl Me Cl Cl Cl Cl Me F Cl Cl Cl Me Cl Br Cl Cl Me F Br Cl Cl Me Cl Me BrCl Me F Me Br Cl Me Cl Cl Br Cl Me F Cl Br Cl Me Cl Br Br Cl Me F Br BrCl Me Cl Me CF₃ Cl i-Pr F Me CF₃ Cl i-Pr Cl Cl CF₃ Cl i-Pr F Cl CF₃ Cli-Pr Cl Br CF₃ Cl i-Pr F Br CF₃ Cl i-Pr Cl Me Cl Cl i-Pr F Me Cl Cl i-PrCl Cl Cl Cl i-Pr F Cl Cl Cl i-Pr Cl Br Cl Cl i-Pr F Br Cl Cl i-Pr Cl MeBr Cl i-Pr F Me Br Cl i-Pr Cl Cl Br Cl i-Pr F Cl Br Cl i-Pr Cl Br Br Cli-Pr F Br Br Cl i-Pr Cl

TABLE 3

R¹ R² R³ R⁴ R⁷ R¹ R² R³ R⁴ R⁷ Me CF₃ F Me F Me CF₃ Cl Me Cl Cl CF₃ F MeF Cl CF₃ Cl Me Cl Br CF₃ F Me F Br CF₃ Cl Me Cl Me Cl F Me F Me Cl Cl MeCl Cl Cl F Me F Cl Cl Cl Me Cl Br Cl F Me F Br Cl Cl Me Cl Me Br F Me FMe Br Cl Me Cl Cl Br F Me F Cl Br Cl Me Cl Br Br F Me F Br Br Cl Me ClMe CF₃ F i-Pr F Me CF₃ Cl i-Pr Cl Cl CF₃ F i-Pr F Cl CF₃ Cl i-Pr Cl BrCF₃ F i-Pr F Br CF₃ Cl i-Pr Cl Me Cl F i-Pr F Me Cl Cl i-Pr Cl Cl Cl Fi-Pr F Cl Cl Cl i-Pr Cl Br Cl F i-Pr F Br Cl Cl i-Pr Cl Me Br F i-Pr FMe Br Cl i-Pr Cl Cl Br F i-Pr F Cl Br Cl i-Pr Cl Br Br F i-Pr F Br Br Cli-Pr ClFormulation/Utility

Compounds of this invention will generally be used as a formulation orcomposition with a carrier suitable for agronomic or nonagronomic usecomprising at least one of a liquid diluent, a solid diluent or asurfactant. The formulation or composition ingredients are selected tobe consistent with the physical properties of the active ingredient,mode of application and environmental factors such as soil type,moisture and temperature. Useful formulations include liquids such assolutions (including emulsifiable concentrates), suspensions, emulsions(including microemulsions and/or suspoemulsions) and the like whichoptionally can be thickened into gels. Useful formulations furtherinclude solids such as dusts, powders, granules, pellets, tablets,films, and the like which can be water-dispersible (“wettable”) orwater-soluble. Active ingredient can be (micro)encapsulated and furtherfowled into a suspension or solid formulation; alternatively the entireformulation of active ingredient can be encapsulated (or “overcoated”).Encapsulation can control or delay release of the active ingredient.Sprayable formulations can be extended in suitable media and used atspray volumes from about one to several hundred liters per hectare.High-strength compositions are primarily used as intermediates forfurther formulation.

The formulations will typically contain effective amounts of activeingredient, diluent and surfactant within the following approximateranges that add up to 100 percent by weight.

Weight Percent Active Ingredient Diluent Surfactant Water-Dispersibleand Water- 5-90  0-94 1-15 soluble Granules, Tablets and Powders.Suspensions, Emulsions, Solutions 5-50 40-95 0-15 (includingEmulsifiable Concentrates) Dusts 1-25 70-99 0-5  Granules and Pellets0.01-99      5-99.99 0-15 High Strength Compositions 90-99   0-10 0-2 

Typical solid diluents are described in Watkins, et al., Handbook ofInsecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books,Caldwell, N.J., Typical liquid diluents are described in Marsden,Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon'sDetergents and Emulsifiers Annual, Allured Publ. Corp., Ridgewood, N.J.,as well as Sisely and Wood, Encyclopedia of Surface Active Agents,Chemical Publ. Co., Inc., New York, 1964, list surfactants andrecommended uses, All formulations can contain minor amounts ofadditives to reduce foam, caking, corrosion, microbiological growth andthe like, or thickeners to increase viscosity.

Surfactants include, for example, polyethoxylated alcohols,polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acidesters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzenesulfonates, organosilicones, N,N-dialkyltaurates, lignin sulfonates,naphthalene sulfonate formaldehyde condensates, polycarboxylates, andpolyoxyethylene/polyoxypropylene block copolymers. Solid diluentsinclude, for example, clays such as bentonite, montmorillonite,attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth,urea, calcium carbonate, sodium carbonate and bicarbonate, and sodiumsulfate. Liquid diluents include, for example, water,N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethyleneglycol, polypropylene glycol, paraffins, alkylbenzenes,alkylnaphthalenes, oils of olive, castor, linseed, tong, sesame, corn,peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters,ketones such as cyclohexanone, 2-heptanone, isophorone and4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol,cyclohexanol, decanol and tetrahydrofurfuryl alcohol.

Solutions, including emulsifiable concentrates, can be prepared bysimply mixing the ingredients. Dusts and powders can be prepared byblending and, usually, grinding as in a hammer mill or fluid-energymill. Suspensions are usually prepared by wet-milling; see, for example,U.S. Pat. No. 3,060,084. Granules and pellets can be prepared byspraying the active material upon preformed granular carriers or byagglomeration techniques. See Browning, “Agglomeration”, ChemicalEngineering, Dec. 4, 1967, pp 147-48, Perry's Chemical Engineer'sHandbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 andfollowing, and PCT Publication WO 91/13546. Pellets can be prepared asdescribed in U.S. Pat. No. 4,172,714. Water-dispersible andwater-soluble granules can be prepared as taught in U.S. Pat. No.4,144,050, U.S. Pat. No. 3,920,442 and DE 3,246,493. Tablets can beprepared as taught in U.S. Pat. No. 5,180,587, U.S. Pat. No. 5,232,701and U.S. Pat. No. 5,208,030. Films can be prepared as taught in GB2,095,558 and U.S. Pat. No. 3,299,566.

For further information regarding the art of formulation, see T. S.Woods, “The Formulator's Toolbox—Product Forms for Modern Agriculture”in Pesticide Chemistry and Bioscience, The Food-Environment Challenge,T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th InternationalCongress on Pesticide Chemistry, The Royal Society of Chemistry,Cambridge, 1999, pp. 120-133, See also U.S. Pat. No. 3,235,361, Col. 6,line 16 through Col. 7, line 19 and Examples 10-41; U.S. Pat. No.3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12,15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182;U.S. Pat. No. 2,891,855, Col. 3, line 66 through Col. 5, line 17 andExamples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons,Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control Handbook,8th Ed., Blackwell Scientific Publications, Oxford, 1989.

In the following Examples, all percentages are by weight and allformulations are prepared in conventional ways. Compound numbers referto compounds in Index Table A.

Example A

Wettable Powder Compound 1 65.0% dodecylphenol polyethylene glycol ether2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0%montmorillonite (calcined) 23.0%.

Example B

Granule Compound 1 10.0% attapulgite granules (low volatile matter,90.0%. 0.71/0.30 mm; U.S.S. No. 25-50 sieves)

Example C

Extruded Pellet Compound 1 25.0% anhydrous sodium sulfate 10.0% crudecalcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0%calcium/magnesium bentonite 59.0%.

Example D

Emulsifiable Concentrate Compound 1 20.0% blend of oil solublesulfonates 10.0% and polyoxyethylene ethers isophorone 70.0%.

Example E

Granule Compound 1 0.5% cellulose 2.5% lactose 4.0% cornmeal 93.0%.

Compounds of this invention are characterized by favorable metabolicand/or soil residual patterns and exhibit activity controlling aspectrum of agronomic and non-agronomic invertebrate pests. Compounds ofthis invention are also characterized by favorable foliar and orsoil-applied systemicity in plants exhibiting translocation to protectfoliage and other plant parts not directly contacted with insecticidalcompositions comprising the present compounds. (In the context of thisdisclosure “invertebrate pest control” means inhibition of invertebratepest development (including mortality) that causes significant reductionin feeding or other injury or damage caused by the pest; relatedexpressions are defined analogously.) As referred to in this disclosure,the term “invertebrate pest” includes arthropods, gastropods andnematodes of economic importance as pests. The term “arthropod” includesinsects, mites, spiders, scorpions, centipedes, millipedes, pill bugsand symphylans. The term “gastropod” includes snails, slugs and otherStylommatophora. The term “nematode” includes all of the helminths, suchas: roundworms, heartworms, and phytophagons nematodes (Nematoda),flukes (Trematoda), Acanthocephala, and tapeworms (Cestoda). Thoseskilled in the art will recognize that not all compounds are equallyeffective against all pests. Compounds of this invention displayactivity against economically important agronomic and nonagronomicpests. The term “agronomic” refers to the production of field crops suchas for food and fiber and includes the growth of cereal crops (e.g.,wheat, oats, barley, rye, rice, maize), soybeans, vegetable crops (e.g.,lettuce, cabbage, tomatoes, beans), potatoes, sweet potatoes, grapes,cotton, and tree fruits (e.g., pome fruits, stone fruits and citrusfruits). The term “nonagronomic” refers to other horticultural (e.g.,forest, greenhouse, nursery or ornamental plants not grown in a field),turf (commercial, golf, residential, recreational, etc.), wood products,public (human) and animal health, domestic and commercial structure,household, and stored product applications or pests. For reason ofinvertebrate pest control spectrum and economic importance, protection(from damage or injury caused by invertebrate pests) of agronomic cropsof cotton, maize, soybeans, rice, vegetable crops, potato, sweet potato,grapes and tree fruit by controlling invertebrate pests are preferredembodiments of the invention. Agronomic or nonagronomic pests includelarvae of the order Lepidoptera, such as armyworms; cutworms, loopers,and heliothines in the family Noctuidae (e.g., fall armyworm (Spodopterafugiperda J. E. Smith), beet armyworm (Spodoptera exigua Hübner); blackcutworm (Agrotis ipsilon Hufuagel), cabbage looper (Trichoplusia niHübner), tobacco budworm (Heliothis virescens Fabricius)); borers,casebearers, webworms, coneworms, cabbageworms and skeletonizers fromthe family Pyralidae (e.g., European corn borer (Ostrinia nubilalisHübner), navel orangeworm (Amyelois transitella Walker), corn rootwebworm (Crambus caliginosellus Clemens), sod webworm (Herpetogrammalicarsisalis Walker)); leafrollers, budworms, seed worms, and fruitworms in the family Torticidae (e.g., codling moth (Cydia pomonellaLinnaeus), grape berry moth (Endopiza viteana Clemens), oriental fruitmoth (Grapholita molesta Busck)); and many other economically importantlepidoptera (e.g., diamondback moth (Plutella xylostella Linnaeus), pinkbollworm (Pectinophora gossypiella Saunders), gypsy moth (Lymantriadispar Linnaeus)); nymphs and adults of the order Blattodea includingcockroaches from the families Blattellidae and Blattidae (e.g., orientalcockroach (Blatta orientalis Linnaeus), Asian cockroach (Blatellaasahinai Mizukabo), German cockroach (Blattella germanica Linnaeus),brownbanded cockroach (Supella longipalpa Fabricius), American cockroach(Periplaneta americana Linnaeus), brown cockroach (Periplaneta brunneaBurmeister), Madeira cockroach (Leucophaea maderae Fabricius)); foliarfeeding larvae and adults of the order Coleoptera including weevils fromthe families Anthribidae, Bruchidae, and Curculionidae (e.g., bollweevil (Anthonomus grandis Boheman), rice water weevil (Lissorhoptrusolyzophilus Kuschel), granary weevil (Sitophilus granarius Linnaeus),rice weevil (Sitophilus oryzae Linnaeus)); flea beetles, cucumberbeetles, rootworms, leaf beetles, potato beetles, and leafminers in thefamily Chrysomelidae (e.g., Colorado potato beetle (Leptinotarsadecemlineata Say), western corn rootworm (Diabrotica virgifera virgiferaLeConte)); chafers and other beetles from the family Scaribaeidae (e.g.,Japanese beetle (Popillia japonica Newman) and European chafer(Rhizotrogus majalis Razoumowsky)); carpet beetles from the familyDermestidae; wireworms from the family Elateridae; bark beetles from thefamily Scolytidae and flour beetles from the family Tenebrionidae. Inaddition agronomic and nonagronomic pests include: adults and larvae ofthe order Dermaptera including earwigs from the family Forficulidae(e.g., European earwig (Forficula auricularia Linnaeus), black earwig(Chelisoches morio Fabricius)); adults and nymphs of the ordersHemiptera and Homoptera such as, plant bugs from the family Miridae,cicadas from the family Cicadidae, leafhoppers (e.g. Empoasca spp.) fromthe family Cicadellidae, planthoppers from the families Fulgoroidae andDelphacidae, treehoppers from the family Membracidac, psyllids from thefamily Psyllidae, whiteflies from the family Aleyrodidae, aphids fromthe family Aphididae, phylloxera from the family Phylloxeridae,mealybugs from the family Pseudococcidae, scales from the familiesCoccidae, Diaspididae and Margarodidae, lace bugs from the familyTingidae, stink bugs from the family Pentatomidae, cinch bugs (e.g.,Blissus spp.) and other seed bugs from the family Lygaeidae, spittlebugsfrom the family Cercopidae squash bugs from the family Coreidae, and redbugs and cotton stainers from the family Pyrrhocoridae. Also included asagronomic and non-agronomic pests are adults and larvae of the orderAcari (mites) such as spider mites and red mites in the familyTetranychidae (e.g., European red mite (Panonychus ulini Koch), twospotted spider mite (Tetranychus urticae Koch), McDaniel mite(Tetranychus mcdanieli McGregor)), flat mites in the familyTenuipalpidae (e.g., citrus flat mite (Brevipalpus Zewisi McGregor)),rust and bud mites in the family Eriophyidae and other foliar feedingmites and mites important in human and animal health, i.e. dust mites inthe family Epidermoptidae, follicle mites in the family Demodicidae,grain mites in the family Glycyphagidae, ticks in the order Ixodidae(e.g., deer tick (Ixodes scapularis Say), Australian paralysis tick(Ixodes holocyclus Neumann), American dog tick (Dermacentor variabilisSay), lone star tick (Amblyomma americanum Linnaeus) and scab and itchmites in the families Psoroptidae, Pyemotidae, and Sarcoptidae; adultsand immatures of the order Orthoptera including grasshoppers, locustsand crickets (e.g., migratory grasshoppers (e.g., Melanoplus sanguinzpesFabricius, M. differentialis Thomas), American grasshoppers (e.g.,Schistocerca americana Drury), desert locust (Schistocerca gregariaForskal), migratory locust (Locusta migratoria Linnaeus), bush locust(Zonocerus spp.), house cricket (Acheta domesticus Linnaeus), molecrickets (Gryllotalpa spp.)); adults and immatures of the order Dipteraincluding leafminers, midges, fruit flies (Tephritidae), frit flies(e.g., Oscinella frit Linnaeus), soil maggots, house flies (e.g., Muscadomestica Linnaeus), lesser house flies (e.g., Fannie canicularisLinnaeus, F. femoralis Stein), stable flies (e.g., Stonioxys caloitransLinnaeus), face flies, horn flies, blow flies (e.g., Chrysomya spp.,Phormia spp.), and other muscoid fly pests, horse flies (e.g., Tabanusspp.), bot flies (e.g., Gastrophilus spp., Oestrus spp.), cattle grubs(e.g., Hypoderma spp.), deer flies (e.g., Chrysops spp.), keds (e.g.,Melophagus ovinus Linnaeus) and other Brachycera, mosquitoes (e.g.,Aedes spp., Anopheles spp., Culex spp.), black flies (e.g., Prosimuliumspp., Simulium spp.), biting midges, sand flies, sciarids, and otherNematocera; adults and immatures of the order Thysanoptera includingonion thrips (Thrips tabaci Lindeman), flower thrips (Frankliniellaspp.), and other foliar feeding thrips; insect pests of the orderHymenoptera including ants (e.g., red carpenter ant (Camponotusferrugineus Fabricius), black carpenter ant (Camponotus pennsylvanicusDe Geer), Pharaoh ant (Monomorium pharaonis Linnaeus), little fire ant(Wasmannia auropunctata Roger), fire ant (Solenopsis geminataFabricius), red imported fire ant (Solenopsis invicta Buren), Argentineant (Iridamyrmex humilis Mayr), crazy ant (Paratrechina longicornisLatreille), pavement ant (Tetramorium caespitum Linnaeus), cornfield ant(Lasius alienus Förster), odorous house ant (Tapinoma sessile Say)),bees (including carpenter bees), hornets, yellow jackets, wasps, andsawflies (Neodiprion spp.; Cephus spp.); insect pests of the orderIsoptera including the eastern subterranean termite (Reticulitermesflavipes Kollar), western subterranean termite (Reticulitermes hesperusBanks), Formosan subterranean termite (Coptotermes formosanus Shiraki),West Indian drywood termite (Incisitermes immigrans Snyder) and othertermites of economic importance; insect pests of the order Thysanurasuch as silverfish (Lepisima saccharina Linnaeus) and firebrat(Thermobia domestica Packard); insect pests of the order Mallophaga andincluding the head louse (Pediculus humanus capitis De Geer), body louse(Pediculus humanus humanus Linnaeus), chicken body louse (Menacanthusstramineus Nitszch), dog biting louse (Trichodectes canis De Geer),fluff louse (Goniocotes gallinae De Geer), sheep body louse (Bovicolaovis Schrank), short-nosed cattle louse (Haematopinus eurysternusNitzsch), long-nosed cattle louse, (Linognathus vituli Linnaeus) andother sucking and chewing parasitic lice that attack man and animals;insect pests of the order Siphonoptera including the oriental rat flea(Xenopsylla cheopis Rothschild), cat flea (Ctenocephalides felisDouche), dog flea (Ctenocephalides canis Curtis), hen flea(Ceratophyllus gallinae Schrank), sticktight flea (Echidnopliagagallinacea Westwood), human flea (Pulex irritans Linnaeus) and otherfleas afflicting mammals and birds. Additional invertebrate pestscovered includeK spiders in the order Araneae such as the brown reclusespider (Loxosceles recluse Gertsch & Mulaik) and the black widow spider(Latrodectus mactans Fabricius), and centipedes in the orderScutigeromorpha such as the house centipede (Scutigera coleoptrataLinnaeus). Compounds of the present invention also have activity onmembers of the Classes Nematoda, Cestoda, Trematoda, and Acanthocephalaincluding economically important members of the orders Strongylida,Ascaridida, Oxyurida, Rhabditida, Spirurida, and Enoplida such as butnot limited to economically important agricultural pests (i.e. root knotnematodes in the genus Meloidogyne, lesion nematodes in the genusPratylenchus, stubby root nematodes in the genus Trichodorus, etc.) andanimal and human health pests (i.e. all economically important flukes,tapeworms, and roundworms, such as Strongylus vulgaris in horses,Toxocara canis in dogs, Haemonchus contortus in sheep, Dirofilariaimmitis Leidy in dogs, Anoplocephala perfoliata in horses, Fasciolahepatica Linnaeus in ruminants, etc.).

Compounds of the invention show particularly high activity against pestsin the order Lepidoptera (e.g., Alabama argillacea Hübner (cotton leafworm), Archips argyrospila Walker (fruit tree leaf roller), A. rosanaLinnaeus (European leaf roller) and other Archips species, Chilosuppressalis Walker (rice stem borer), Cnaphalocrosis medinalis Guenee(rice leaf roller), Crambus caliginosellus Clemens (corn root webworm),Crambus teterrellus Zincken (bluegrass webworm), Cydia pomonellaLinnaeus (codling moth), Earias insulana Boisduval (spiny bollworm),Earias vittella Fabricius (spotted bollworm), Helicoverpa armigeraHübner (American bollworm), Helicoverpa zea Boddie (corn earworm),Heliothis virescens Fabricius (tobacco budworm), Herpetogrammalicarsisalis Walker (sod webworm), Lobesia botrana Denis &Schiffermüller (grape berry moth), Pectinophora gossypiella Sanders(pink bollworm), Phyllocnistis citrella Stainton (citrus leafminer),Pieris brassicae Linnaeus (large white butterfly), Pieris rapae Linnaeus(small white butterfly), Plutella xylostella Linnaeus (diamondbackmoth), Spodoptera exigua Hübner (beet armyworm), Spodoptera lituraFabricius (tobacco cutworm, cluster caterpillar), Spodoptera frugiperdaJ. E. Smith (fall armyworm), Trichoplusia ni Hübner (cabbage looper) andTuta absoluta Meyrick (tomato leafminer)). Compounds of the inventionalso have commercially significant activity on members from the orderHomoptera including: Acyrthisiphon pisum Harris (pea aphid), Aphiscraccivora Koch (cowpea aphid), Aphis fabae Scopoli (black bean aphid),Aphis gossypii Glover (cotton aphid, melon aphid), Aphis pomi De Geer(apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solaniKaltenbach (foxglove aphid), Chaetosiphon fragaefolii Cockerell(strawberry aphid), Diuraphis noxia Kurdjumov/Mordvilko (Russian wheataphid), Dysaphis plantaginea Paaserini (rosy apple aphid); Eriosomalanigerum Hausmann (woolly apple aphid), Hyalopterus pruni Geoffloy(mealy plum aphid), Lipaphis erysimi Kaltenbach (turnip aphid),Metopolophium dirrhodum Walker (cereal aphid), Macrosipum eziphorbiczeThomas (potato aphid), Myzus persicae Sulzer (peach-potato aphid, greenpeach aphid), Nasonovia ribisnigri Mosley (lettuce aphid), Pemphigusspp. (root aphids and gall aphids), Rhopalosiphum maidis Fitch (cornleaf aphid), Rhopaloszphum padi Linnaeus (bird cherry-oat aphid),Schizaphis grarninum Rondani (greenbug), Sitobion avenae Fabricius(English grain aphid), Therioaphis maculate Buckton (spotted alfalfaaphid), Toxoptera aurantii Boyer de Fonscolombe (black citrus aphid),and Toxoptera citricida Kirkaldy (brown citrus aphid); Adelges spp.(adelgids); Phylloxera devastairix Pergaude (pecan phylloxera); Bemisiatabaci Germadius (tobacco whitefly, sweetpotato whitefly), Bemisiaargentifolii Bellows & Perring (silverleaf whitefly), Dialeurodes cirriAshmead (citrus whitefly) and Trialeurodes vaporariorum Westwood(greenhouse whitefly); Empoasca fabae Harris (potato leafhopper),Laodelphax striatellus Fallen (smaller brown planthopper), Macrolestesquadrilineatus Forbes (aster leafhopper), Nephotehtx cinticeps Uhler(green leafhopper), Nephotettix nigropktus Stål (rice leafhopper),Nilaparvata lugens Stål (brown planthopper), Peregrinus maidis Ashmead(corn planthopper), Sogatella furcifera Horvath (white-backedplanthopper), Sogatodes orizicola Muir (rice delphacid), Typhlocybapomaria McAtee white apple leafhopper, Erythroneoura spp. (grapeleafhoppers); Magicidada septendecim Linnaeus (periodical cicada);Icerya purchasi Maskell (cottony cushion scale), Quadraspidiotusperniciosus Comstock (San Jose scale); Planococcus cirri Risso (citrusmealybug); Pseudococcus spp. (other mealybug complex); Cacopsyllapyricola Foerster (pear psylla), Trioza diospyri Ashmead (persimmonpsylla). These compounds also have activity on members from the orderHemiptera Acrosternum hilare Say (green, stink bug), Anasa tristis DeGeer (squash bug), Blissus leucopterus leucopterus Say (chinch bug),Corythuca gossypii Fabricius (cotton lace bug), Cyrtopeitis modestaDistant (tomato bug), Dysdercus suturellus Herrich-Schäffer (cottonstainer), Euchistus servus Say (brown stink bug), Euchistus variolariusPalisot de Beauvois (one-spotted stink bug), Graptosthetus spp. (complexof seed bugs), Leptoglossus corculus Say (leaf-footed pine seed bug),Lygus lineolaris Palisot de Beauvois (tarnished plant bug), Nezaraviridula Linnaeus (southern green stink bug), Oebalus pugnax Fabricius(rice stink bug), Oncopeitus fasciatus Dallas (large milkweed bug),Pseudatomoscelis seriatus Router (cotton fleahopper). Other insectorders controlled by compounds of the invention include Thysanoptera(e.g., Frankliniella occidentalis Pergande (western flower thrip),Scirthothrips citri Moulton (citrus thrip), Sericothrips variabilisBeach (soybean thrip), and Thrips tabaci Lindeman (onion thrip); and theorder Coleoptera (e.g., Leptinotarsa decemlineata Say (Colorado potatobeetle), Epilachna varivestis Mulsant (Mexican bean beetle) andwireworms of the genera Agriotes, Athous or Limonius).

Compounds of this invention can also be mixed with one or more otherbiologically active compounds or agents including insecticides,fungicides, nematocides, bactericides, acaricides, growth regulatorssuch as rooting stimulants, chemosterilants, semiochemicals, repellents,attractants, pheromones, feeding stimulants, other biologically activecompounds or entomopathogenic bacteria, virus or fungi to form amulti-component pesticide giving an even broader spectrum of agronomicand non-agronomic utility. Thus the present invention also pertains to acomposition comprising a biologically effective amount of a compound ofFormula 1 and an effective amount of at least one additionalbiologically active compound or agent and can further comprise at leastone of a surfactant, a solid diluent or a liquid diluent. Examples ofsuch biologically active compounds or agents with which compounds ofthis invention can be formulated are: insecticides such as abamectin,acephate, acetamiprid, acetoprole, amidoflumet (S-1955), avermectin,azadirachtin, azinphos-methyl, bifenthrin, bifenazate, bistrifluoron,buprofezin, carbofuran, chlorfenapyr, chlorofluazuron, chlorpyrifos,chlorpyrifos-methyl, chromafenozide, clothianidin, cyfluthrin,beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin,cyromazine, deltamethrin, diafenthiuron, diazinon, diflubenzuron,dimethoate, denotefuran, diofenolan, enamectin, endosulfan,esfenvalerate, ethiprole, fenothicarb, fenoxycarb, fenpropathrin,fenvalerate, fipronil, flonicamid, flucythrinate, tan-fluvalinate,flufenerim (UR-50701), flufenoxuron, gamma-chalothrin, halofenozide,hexaflumuron, imidacloprid, indoxacarb, isofenphos, lufenuron,malathion, metaldehyde, methamidophos, methidathion, methomyl,methoprene, methoxychlor, methoxyfenozide, metoflurthrin, monocrotophos,methoxyfenozide, novaluron, noviflumuron (XDE-007), oxamyl, parathion,parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon,pirimicarb, profenofos, profluthrin, protrifenbute, pymetrozine,pyridalyl, pyriproxyfen, rotenone, S1812 (Valent) spinosad, spiromesifen(BSN 2060), sulprofos, tebufenozide, teflubenzuron, tefluthrin,terbufos, tetrachlorvinphos, thiacloprid, thiarnethoxam, thiodicarb,thiosultap-sodium, tolfenpyrad, tralomethrin, trichlorfon andtriflnmuron; fungicides such as acibenzolar, S-methyl, azoxystrobin,benalazy-M, benthiavalicarb, benomyl, blasticidin-S, Bordeaux mixture(tribasic copper sulfate), boscalid, bromuconazole, buthiobate,carpropamid, captafol, captan, carbendazim, chloroneb, chlorothalonil,clotrimazole, copper oxychloride, copper salts, cymoxanil, cyazofamid,cyflufenamid, cyproconazole, cyprodinil, diclocymet, diclomezine,dicloran, difenoconazole, dimetliomorph, ditnoxystrobin, diniconazole,diniconazole-M, dodine, edifenphos, epoxiconazole, ethaboxam,famoxadone, fenarimol, fenbuconazole, fenhexamid, fenoxanil,fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentinhydroxide, fluazinam, fludioxonil, flumorph, fluoxastrobin,fluquinconazole, flusilazole, flutolanil, flutriafol, folpet,fosetyl-aluminum, furalaxyl, furametapyr, guazatine, hexaconazole,hymexazol, imazalil, imibenxonazole, iminoctadine, ipconazole,iprobenfos, iprodione, iprovalicarb, isoconazole, isoprothiolane,kasugamycin, kresoxim-methyl, mancozeb, maneb, mefenoxam, mepanapyrim,mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin,metrafenone, miconazole, myclobutanil, neo-asozin (ferricmethanearsonate), nuarimol, oryzastrobin, oxadixyl, oxpoconazole,penconazole, pencycuron, picobenzamid, picoxystrobin, probenazole,prochloraz, propamocarb, propiconazole, proquinazid, prothioconazole,pyraclostrobin, pyrimethanil, pyrifenox, pyroquilon, quinoxyfen,silthiofam, simeconazole, sipconazole, spiroxamine, sulfur,tebuconazole, tetraconazole, tiadinil, thiabendazole, thifluzamide,thiophanate-methyl, thiram, tolylfluanid, triadiniefon, triadimenol,triarimol, tricyclazole, trifloxystrobin, triflumizole, triforine,triticonazole, uniconazole, validamycin, vinclozolin and zoxamicle;nematocides such as aldicarb, oxamyl and fenamiphos; bactericides suchas streptomycin; acaricides such as amitraz, chinomethionat,chlorobenzilate, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin,fenbutatin oxide, fenpropathrin, fenpyroximate, hexythiazox, propargite,pyridaben and tebufenpyrad; and biological agents such as Bacillusthuringiensis including ssp. aizawai and kurstaki, Bacillusthuringiensis delta endotoxin, baculovirus, and entomopathogenicbacteria, virus and fungi. Compounds of this invention and compositionsthereof can be applied to plants genetically transformed to expressproteins toxic to invertebrate pests (such as Bacillus thuringiensistoxin). The effect of the exogenously applied invertebrate pest controlcompounds of this invention may be synergistic with the expressed toxinproteins.

A general reference for these agricultural protectants is The PesticideManual, 12th Edition, C. D. S. Tomlin, Ed., British Crop ProtectionCouncil, Farnham, Surrey, U.K., 2000.

Preferred insecticides and acaricides for mixing with compounds of thisinvention include pyrethroids such as acetamiprid, cypermethrin,cyhalothrin, cyfluthrin, beta-cyfluthrin, esfenvalerate, fenvalerate andtralomethrin; carbamates such as fenothicarb, methomyl, oxamyl andthiodicarb; neonicotinoids such as clothianidin, imidacloprid andthiacioprid; neuronal Sodium channel blockers such as indoxacarb;insecticidal macrocyclic lactones such as spinosad, abamectin,avermectin and emamectin; γ-aminobutyric acid (GABA) antagonists such asendosulfan, ethiprole and fipronil; insecticidal ureas such asflufenoxuron and triflumuron; juvenile hormone mimics such as diofenolanand pyriproxyfen; pymetrozine; and amitraz. Preferred biological agentsfor mixing with compounds of this invention include Bacillusthuringiensis and Bacillus thuringiensis delta endotoxin as well asnaturally occurring and genetically modified viral insecticidesincluding members of the family Baculoviridae as well as entomophagousfungi.

Most preferred mixtures include a mixture of a compound of thisinvention with cyhalothrin; a mixture of a compound of this inventionwith beta-cyfluthrin; a mixture of a compound of this invention withesfenvalerate; a mixture of a compound of this invention with methomyl;a mixture of a compound of this invention with imidacloprid; a mixtureof a compound of this invention with thiacloprid; a mixture of acompound of this invention with indoxacarb; a mixture of a compound ofthis invention with abamectin; a mixture of a compound of this inventionwith endosulfan; a mixture of a compound of this invention withethiprole; a mixture of a compound of this invention with fipronil; amixture of a compound of this invention with flufenoxuron; a mixture ofa compound of this invention with pyriproxyfen; a mixture of a compoundof this invention with pymetrozine; a mixture of a compound of thisinvention with amitraz; a mixture of a compound of this invention withBacillus thuringiensis aizawai or Bacillus thuringiensis kurstaki, and amixture of a compound of this invention with Bacillus thuringiensisdelta endotoxin.

In certain instances, combinations with other invertebrate pest controlcompounds or agents having a similar spectrum of control but a differentmode of action will be particularly advantageous for resistancemanagement. Thus, compositions of the present invention can furthercomprise a biologically effective amount of at least one additionalinvertebrate pest control compound or agent having a similar spectrum ofcontrol but a different mode of action. Contacting a plant geneticallymodified to express a plant protection compound (e.g., protein) or thelocus of the plant with a biologically effective amount of a compound ofinvention can also provide a broader spectrum of plant protection and beadvantageous for resistance management.

Invertebrate pests are controlled in agronomic and nonagronomicapplications by applying one or more of the compounds of this invention,in an effective amount, to the environment of the pests including theagronomic and/or nonagronomic locus of infestation, to the area to beprotected, or directly on the pests to be controlled. Thus, the presentinvention further comprises a method for the control of invertebrates inagronomic and/or nonagronomic applications, comprising contacting theinvertebrates or their environment with a biologically effective amountof one or more of the compounds of the invention, or with a compositioncomprising at least one such compound or a composition comprising atleast one such compound and an effective amount of at least oneadditional biologically active compound or agent. Examples of suitablecompositions comprising a compound of the invention and an effectiveamount of at least one additional biologically active compound or agentinclude granular compositions wherein the additional biologically activecompound is present on the same granule as the compound of the inventionor on granules separate from those of the compound of this invention.

A preferred method of contact is by spraying. Alternatively, a granularcomposition comprising a compound of the invention can be applied to theplant foliage or the soil. Compounds of this invention are alsoeffectively delivered through plant uptake by contacting the plant witha composition comprising a compound of this invention applied as a soildrench of a liquid formulation, a granular formulation to the soil, anursery box treatment or a dip of transplants. Compounds are alsoeffective by topical application of a composition comprising a compoundof this invention to the locus of infestation. Other methods of contactinclude application of a compound or a composition of the invention bydirect and residual sprays, aerial sprays, gels, seed coatings,microencapsulations, systemic uptake, baits, eartags, boluses, foggers,fumigants, aerosols, dusts and many others. The compounds of thisinvention may also be impregnated into materials for fabricatinginvertebrate control devices (e.g. insect netting).

A compound of this invention can be incorporated into a bait compositionthat is consumed by an invertebrate pest or used within devices such astraps, bait stations, and the like. Such a bait composition can be inthe form of granules which comprise (a) an active ingredient, namely acompound of Formula 1, an N-oxide, or salt thereof, (b) one or more foodmaterials, (c) optionally an attractant, and (d) optionally one or morehumectants. Of note granules or bait compositions which comprise betweenabout 0.001-5% active ingredient; about 40-99% food material and/orattractant; and optionally about 0.05-10% humectants; are effective incontrolling soil invertebrate pests at very low application rates,particularly at doses of active ingredient that are lethal by ingestionrather than by direct contact. Of note some food materials will functionboth as a food source and an attractant. Food materials includecarbohydrates, proteins and lipids. Examples of food materials arevegetable flour, sugar, starches, animal fat, vegetable oil, yeastextracts and milk solids. Examples of attractants are odorants andflavorants, such as fruit or plant extracts, perfume, or other animal orplant component, pheromones or other agents Down to attract a targetinvertebrate pest. Examples of humectants, i.e. moisture retainingagents, are glycols and other polyols, glycerine and sorbitol. Of noteis a bait composition (and a method utilizing such a bait composition)used to control invertebrate pests including individually or incombinations ants, termites, and cockroaches. A device for controllingan invertebrate pest can comprise the present bait composition and ahousing adapted to receive the bait composition, wherein the housing hasat least one opening sized to permit the invertebrate pest to passthrough the opening so the invertebrate pest can gain access to the baitcomposition from a location outside the housing, and wherein the housingis further adapted to be placed in or near a locus of potential or knownactivity for the invertebrate pest.

The compounds of this invention can be applied in their pure state, butmost often application will be of a formulation comprising one or morecompounds with suitable carriers, diluents, and surfactants and possiblyin combination with a food depending on the contemplated end use Apreferred method of application involves spraying a water dispersion orrefined oil solution of the compounds. Combinations with spray oils,spray oil concentrations, spreader stickers, adjuvants, other solvents,and synergists such as piperonyl butoxide often enhance compoundefficacy. For nonagronomic uses such sprays can be applied from spraycontainers such as a can, a bottle or ether container, either by meansof a pump or by releasing it from a pressurized container, e.g. apressurized aerosol spray can. Such spray compositions can take variousfauns, for example, sprays, mists, foams, fumes or fog. Such spraycompositions thus can further comprise propellants, foaming agents, etc.as the case may be. Of note is a spray composition comprising a compoundor composition of the present invention and a propellant. Representativepropellants include, but are not limited to, methane, ethane, propane,iospropane, butane, isobutane, butene, pentane, iospentane, neopentane,pentene, hydrofluorocarbons, chlorofluoroacarbons, dimethyl ether, andmixtures of the foregoing. Of note is a spray composition (and a methodutilizing such a spray composition dispensed from a spray container)used to control an invertebrate pest including individually or incombinations mosquitoes, black flies, stable flies, deer flies, horseflies, wasps, yellow jackets, hornets, ticks, spiders, ants, gnats, andthe like.

The rate of application required for effective control (i.e.“biologically effective amount”) will depend on such factors as thespecies of invertebrate to be controlled, the pest's life cycle, lifestage, its size, location, time of year, host crop or animal, feedingbehavior, mating behavior, ambient moisture, temperature, and the like.Under normal circumstances, application rates of about 0.01 to 2 kg ofactive ingredient per hectare are sufficient to control pests inagronomic ecosystems, but as little as 0.0001 kg/hectare may besufficient or as much as 8 kg/hectare may be required. For nonagronomicapplications, effective use rates will range from about 1.0 to 50mg/square meter but as little as 0.1 mg/square meter may be sufficientor as much as 150 mg/square meter may be required. One skilled in theart can easily determine the biologically effective amount necessary forthe desired level of invertebrate pest control.

The following TESTS demonstrate the control efficacy of compounds ofthis invention on specific pests. “Control efficacy” representsinhibition of invertebrate pest development (including mortality) thatcauses significantly reduced feeding. The pest control protectionafforded by the compounds is not limited, however, to these species. SeeIndex Table A, B and C for compound descriptions. The followingabbreviations are used in the Index Tables which follow: i is iso, t istertiary, Me is methyl, Et is ethyl, Pr is propyl, i-Pr is, isopropyl,c-Pr is cyclopropyl, Bu is butyl, and CN is cyano. The abbreviation“Ex.” stands for “Example” and is followed by a number indicating inwhich example, the compound is prepared.

INDEX TABLE A

Com- m.p. pound R¹ R² R³ R⁴ R⁵ (° C.)  1 Me CF₃ Cl H H 200-202 (Ex. 1) 2 Me CE₃ Cl Me H 214-216 (Ex. 2)  3 Me Cl Cl Me H * (Ex. 3)  4 Me Cl ClH H >255 (Ex. 4)  5 Me Br Cl Me H * (Ex. 5)  6 Me Br Cl H H >255 (Ex. 6) 7 Cl Cl Cl Me H 197-200 (Ex. 7)  8 Me CF₃ Cl i-Pr H >250  9 Cl Cl Cli-Pr H 213-215 10 Cl Br Cl i-Pr H 222-225 11 Cl Br Cl i-Pr Me 224-226 12Cl Br Cl Me H 198-201 13 Cl Cl Cl i-Pr Me 238-241 14 Cl Br Cl H H >25515 Cl F Cl i-Pr H 162-166 16 Cl F Cl Me H 205-208 17 Cl Br F i-Pr H230-232 18 Cl Br F Me H * 19 Cl Br F H H >255 20 Me CF₃ Cl Me Me 227-23021 Cl CF₃ Cl i-Pr H 247-249 22 Cl CF₃ Cl Me H 215-217 23 Cl CF₃ Cl HH >255 24 Me Cl Cl i-Pr H * 25 Me Br Cl i-Pr H * 26 Me Cl Cl CH₂CN H213-215 27 Me Br Cl CH₂CN H 225-227 28 Me OCH₂CF₃ Cl Me Me 132-135 29 MeOCH₂CF₃ Cl Me H 162-165 30 Me CF₃ Cl t-Bu H >250 31 Me CF₃ Cl CH₂CN H250-251 32 Me CF₃ Cl Et H 150-151 33 Me Cl Cl Et H * 34 Me Cl Cl t-BuH >255 35 Me Br Cl Et H * 36 Me Br Cl t-Bu H >255 37 Me CF₃ ClCH(CH₃)CH₂SMe H 208-209 39 Me Br Cl Me Me 262-264 40 Me OCH₂CF₃ Cl i-PrH 164-167 41 Me OCH₂CF₃ Cl t-Bu H * 42 Me OCH₂CF₃ Cl Me Me 212-214 43 MeOCH₂CF₃ Cl Et H 168-171 44 Me OCH₂CF₃ Cl CH₂CN H 207-211 45 Me Cl Cl MeMe 261-263 46 Me CF₃ F Me H 211-212 47 Me CF₃ F H H 138-139 48 Me CF₃ FEt H 219-220 49 Me Br F Me H 152-153 50 Me Br F H H 162-164 51 Me Br FEt H 201-202 52 Me CF₃ F i-Pr H 229-230 53 Me Br F i-Pr H 159-160 54 MeCF₃ F CH(CH₃)CH₂SMe H 209-210 55 F Br Cl Me H 209-210 63 Me Br ClCH(CH₃)CH₂SMe H 180-181 64 Me Cl Cl CH(CH₃)CH₂SMe H 193-194 65 Me Br ClC(CH₃)₂CH₂SMe H 161-162 66 Me CF₃ Cl C(CH₃)₂CH₂SMe H 250-250 67 Me Cl ClC(CH₃)₂CH₂SMe H 234-235 68 Me CF₃ Cl c-Pr H 159-160 69 Me CF₃ Cl(CH₂)₂OMe H 206-207 70 Me Cl Cl c-Pr H 156-157 71 Me Cl Cl (CH₂)₂OMe H118-119 72 Me Br Cl (CH₂)₂OMe H 216-217 73 Me Br Cl c-Pr H 159-160 74 MeCF₃ Cl Me H 235-236 75 Me CF₃ Cl CH₂CH(CH₃)₂ H 257-258 76 Me Br ClCH₂(c-Pr) H 223-224 77 Me Br Cl CH₂CH(CH₃)₂ H 245-246 78 Me Br ClCH(CH₃)CH₂S(O)Me H 157-158 79 Me Br Cl CH(CH₃)CH₂S(O)₂Me H 169-170 80 MeCl Cl CH(CH₃)(CH₂)₂SMe H 190-191 81 Me Br Cl CH(CH₃)(CH₂)₂SMe H 188-19082 Me CF₃ Cl CH(CH₃)(CH₂)₂SMe H 134-135 83 Me Cl Cl CH(CH₃)(CH₂)₂S(O)₂MeH 186-187 84 Me Br Cl CH(CH₃)(CH₂)₂S(O)₂Me H 182-183 85 Br Br Cl Me H214-215 86 Br Br Cl i-Pr H 166-167 87 Br Br Cl CH₂CN H 226-227 88 Me ClF Me H 149-150 89 Me Cl F H H 146-147 90 Me Cl Br H H 189-190 91 Me ClBr Me H 149-150 92 Me Cl Br i-Pr H 119-120 93 Me Cl Br Me Me 247-248 94Me Br Br H H 255-256 95 Me Br Br Me H 183-184 96 Me Br Br i-Pr H 235-23697 Me Br Br Me Me 242-243 *See Index Table C for ¹H NMR data.

INDEX TABLE B

Compound R¹ R² R³ R⁴ R⁵ R⁶ R⁷ m.p. (° C.)  98 Me Br Cl Me H H Cl 145-146 99 Me Br Cl Et H H Cl 148-149 100 Me Br Cl i-Pr H H Cl 174-175 101 MeCl Cl Et H H Cl 167-168 102 Me Cl Cl i-Pr H H Cl 189-190 103 Me Cl Cl MeH H Cl 185-186 104 Me Br Cl Me H F H 152-153 105 Me Br Cl i-Pr H F H134-136 106 Me Cl F H H H F 212-213 107 Me Cl F Me H H F 214-215 108 MeBr F H H H F 204-205 109 Me Br F Me H H P 222-223 110 Me Br F Et H H P200-201 111 Me Br F i-Pr H H F 203-204 112 Me Cl F Et H H F 195-196

INDEX TABLE C Cmpd No. ¹H NMR Data (CDCl₃ solution unless indicatedotherwise) 3 (CDCl₃) 10.55 (s, 1H), 8.45 (d, 1H), 7.85 (dd, 1H), 7.55(s, 2H), 7.40 (dd, 1H), 6.97 (s, 1H), 6.30 (b q, 1H), 2.98 (d, 3H), 2.24(s, 3H) 5 (CDCl₃) 10.55 (s, 1H), 8.45 (d, 1H), 7.85 (dd, 1H), 7.57 (m,2H), 7.37 (dd, 1H), 7.05 (s, 1H), 6.30 (b q, 1H) 2.98 (d, 3H), 2.24 (s,3H) 18 (CDCl₃) 10.10 (br s, 1H), 8.38 (d, 1H), 7.75 (s, 1H), 7.65 (s,1H), 7.60 (m, 1H), 7.34 (m, 1H), 7.10 (s, 1H), 6.58 (b q, 1H) 2.96 (s,3H) 24 (CDCl₃) 10.12 (s, 1H), 8.56 (d, 1H), 7.85 (d, 1H), 7.58 (m, 2H),7.40 (dd, 1H), 6.97 (s, 1H), 6.00 (b d, 1H) 4.22 (m, 1H), 2.25 (s, 3H),1.26 (d, 6H) 25 (CDCl₃) 10.60 (s, 1H), 8.47 (d, 1H), 7.85 (dd, 1H), 7.56(s, 2H), 7.39 (dd, 1H), 7.06 (s, 1H), 6.04 (b d, 1H) 4.20 (m, 1H), 2.24(s, 3H), 1.26 (s, 6H) 33 (CDCl₃) 10.60 (s, 1H), 8.45 (d, 1H), 7.85 (d,1H), 7.58 (s, 2H), 7.39 (m, 1H), 6.97 (s, 1H), 6.20 (b t, 1H) 3.46 (m,2H), 2.25 (s, 3H), 1.25 (t, 3H) 35 (CDCl₃) 10.60 (s, 1H), 8.46 (d, 1H),7.85 (d, 1H), 7.57 (s, 2H), 7.38 (m, 1H), 7.05 (s, 1H), 6.25 (b t, 1H)3.46 (m, 2H), 2.24 (s, 3H), 1.25 (t, 3H) 41 (CDCl₃) 10.40 (s, 1H), 8.47(d, 1H), 7.85 (d, 1H), 7.50 (s, 2H), 7.37 (dd, 1H), 6.63 (s, 1H), 5.97(s, 1H) 4.68 (q, 2H), 1.42 (s, 9H)

Biological Examples of the Invention Test A

For evaluating control of diamondback moth (Plutella xylostella) thetest unit consisted of a small open container with a 12-14-day-oldradish plant inside. This was pre-infested with 10-45 neonate larvae ona piece of insect diet by use of a core sampler to remove a plug from asheet of hardened insect diet having many larvae growing on it andtransfer the plug containing larvae and diet to the test unit. Thelarvae moved onto the test plant as the diet plug dried out.

Test compounds were formulated using a solution containing 10% acetone,90% water and 300 ppm X-77® Spreader Lo-Foam Formula non-ionicsurfactant containing alkylarylpolyoxyethylene, free fatty acids,glycols and isopropanol (Loveland Industries, Inc. Greeley, Colo., USA).The formulated compounds were applied in 1 mL of liquid through a SUJ2atomizer nozzle with ⅛ JJ custom body (Spraying Systems Co. Wheaton,USA) positioned 1.27 cm (0.5 inches) above the top of each test unit.All experimental compounds in these tests were sprayed at 50 ppmreplicated three times. After spraying of the formulated test compound,each test unit was allowed to dry for 1 hour and then a black, screenedcap was placed on top. The test units were held for 6 days in a growthchamber at 25° C. and 70% relative humidity. Plant feeding damage wasthen visually assessed based on foliage consumed.

Of the compounds tested the following provided very good to excellentlevels of plant protection (20% or less feeding damage): 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 88, 89,90, 91, 92, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 106, 108, 109,110, 111 and 112.

Test B

For evaluating control of fall armyworm (Spodoptera frugiperda) the testunit consisted of a small open container with a 4-5-day-old corn (maize)plant inside. This was pre-infested (using a core sampler) with 10-151-day-old larvae on a piece of insect diet.

Test compounds were formulated and sprayed at 50 ppm as described forTest A. The applications were replicated three times. After spraying,the test units were maintained in a growth chamber and then visuallyrated as described for Test A.

Of the compounds tested, the following provided excellent levels ofplant protection (20% or less feeding damage): 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 63, 64, 65, 66, 67, 68, 70, 73,74, 76, 78, 88, 91, 92, 94, 95, 96, 98, 99, 100, 101, 102, 103, 106,109, 110, 111 and 112.

Test C

For evaluating control of green peach aphid (Myzus persicae) throughcontact and/or systemic means, the test unit consisted of a small opencontainer with a 12-15-day-old radish plant inside. This waspre-infested by placing on a leaf of the test plant 30-40 aphids on apiece of leaf excised from a culture plant (cut-leaf method). The larvaemoved onto the test plant as the leaf piece desiccated. Afterpre-infestation, the soil of the test unit was covered with a layer ofsand.

Test compounds were formulated using a solution containing 10% acetone,90% water and 300 ppm X-77® Spreader Lo-Foam Formula non-ionicsurfactant containing alkylarylpolyoxyethylene, free fatty acids,glycols and isopropanol (Loveland Industries, Inc.). The formulatedcompounds were applied in 1 mL of liquid through a SUJ2 atomizer nozzlewith ⅛ JJ custom body (Spraying Systems Co.) positioned 1.27 cm (0.5inches) above the top of each test unit, All experimental compounds inthis screen were sprayed at 250 ppm, replicated three times. Afterspraying of the formulated test compound, each test unit was allowed todry for 1 hour and then a black, screened cap was placed on top. Thetest units were held for 6 days in a growth chamber at 19-21° C. and50-70% relative humidity. Each test unit was then visually assessed forinsect mortality.

Of the compounds tested, the following resulted in at least 80%mortality: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 40, 41, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 63,65, 66, 67, 68, 69, 70, 73, 74, 76, 78, 88, 89, 90, 91, 92, 94, 95, 96,98, 99, 100, 101, 102, 103, 106, 108, 109, 110, 111 and 112.

Test D

For evaluating control of potato leafhopper (Empoasca fabae Harris)through contact and/or systemic means, the test unit consisted of asmall open container with a 5-6 day old Longio bean plant (primaryleaves emerged) inside. White sand was added to the top of the soil andone of the primary leaves was excised prior to application. Testcompounds were formulated and sprayed at 250 ppm and replicated threetimes as described for Test C. After spraying, the test units wereallowed to dry for 1 hour before they were post-infested with 5 potatoleafhoppers (18 to 21 day old adults). A black, screened cap was placedon the top of the cylinder. The test units were held for 6 days in agrowth chamber at 19-21° C. and 50-70% relative humidity. Each test unitwas then visually assessed for insect mortality.

Of the compounds tested, the following resulted in at least 80%mortality: 1, 3, 4, 5, 6, 8, 10, 12, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 32, 33, 34, 35, 37, 38, 40, 41, 43, 44, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 63, 66, 67, 68, 70, 73, 76, 88, 89, 90,94, 95, 98, 99, 101, 103, 106, 108, 109, 110, 111 and 112.

Test E

For evaluating control of cotton melon aphid (Aphis gossypii) throughcontact and/or systemic means, the test unit consisted of a small opencontainer with a 6-7-day-old cotton plant inside. This was pro-infestedwith 30-40 insects on a piece of leaf according to the cut-leaf methoddescribed for Test C, and the soil of the test unit was covered with alayer of sand.

Test compounds were formulated and sprayed at 250 ppm as described forTest D. The applications were replicated three times. After spraying,the test units were maintained in a growth chamber and then visuallyrated as described for Test D.

Of the compounds tested, the following resulted in at least 80%mortality: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 63, 69,71, 72, 74, 76, 78, 79, 81, 84, 88, 89, 90, 91, 92, 95, 96, 97, 98, 99,100, 101, 102, 103, 106, 108, 109, 110, 111 and 112.

Test F

For evaluating control of corn planthopper (Peregrinus maidis) throughcontact and/or systemic means, the test unit consisted of a small opencontainer with a 3-4 day old corn (maize) plant (spike) inside. Whitesand was added to the top of the soil prior to application. Testcompounds were formulated and sprayed at 250 ppm and replicated threetimes as described for Test C. After spraying, the test units wereallowed to dry for 1 hour before they were post-infested with 10-20 cornplanthoppers (18- to 20-day old nymphs) by sprinkling them onto the sandwith a salt shaker. A black, screened cap was placed on the top of thecylinder. The test emits were held for 6 days in a growth chamber at19-21° C. and 50-70% relative humidity. Each test unit was then visuallyassessed for insect mortality.

Of the compounds tested, the following resulted in at least 80%mortality: 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 18, 20, 24, 25, 26,27, 28, 29, 32, 33, 35, 37, 38, 39, 40, 41, 43, 45, 46, 47, 48, 49, 50,51, 53, 56, 88, 89, 90, 91, 94, 95, 108 and 109.

Test G

For evaluating control of silverleaf whitefly (Bemisia tabaci), the testunit consisted of a 14-21-day-old cotton plant grown in Redi-earth®media (Scotts Co.) with at least two true leaves infested with 2nd and3rd instar nymphs on the underside of the leaves.

Test compounds were formulated in no more than 2 mL of acetone and thendiluted with water to 25-30 mL. The formulated compounds were appliedusing a flat fan air-assisted nozzle (Spraying Systems 122440) at 10 psi(69 kPa). Plants were sprayed to run-off on a turntable sprayer. Allexperimental compounds in this screen were sprayed at 250 ppm andreplicated three times. After spraying of the test compound, the testunits were held for 6 days in a growth chamber at 50-60% relativehumidity and 28° C. daytime and 24° C. nighttime temperature. Then theleaves were removed and the dead and live nymphs were counted tocalculate percent mortality.

Of the compounds tested, the following resulted in at least 80%mortality: 2, 3, 4, 5, 7, 8, 9, 10, 24, 25, 26, 27, 28, 30, 32, 33, 34,35, 38, 41, 46, 48, 49, 51, 52, 53, 66, 67, 70, 73, 88, 92 and 98.

Test H

For evaluating movement of compounds in plants and control of greenpeach aphid (Myzus persicae) and potato leafhopper (Empoasca fabae)after foliar movement of compound through the plant, the test unitconsisted of a small open container with a 12-15-day-old radish plant(for green peach aphid test) or 5-6 day old Longio bean plant (forpotato leafhopper test).

Test compounds were formulated using a solution containing 10% acetone,90% water and 600 ppm X-770 Spreader Lo-Foam Formula non-ionicsurfactant containing alkylarylpolyoxyethylene, free fatty acids,glycols and isopropanol (Loveland Industries, Inc.). The formulatedcompounds were applied in 20 microliters by pipet to two largerphotosynthetically active leaves. All experimental compounds in thisscreen were applied at 1000 ppm, and the tests were replicated threetimes. After applying the formulated test compounds, the soil of eachtest unit was covered with a layer of sand and each test unit wasallowed to dry for 1 hr and then a black, screened cap was placed ontop. The test units were held in a growth chamber at about 20° C. and50-70% relative humidity.

After 2 days, the treated leaves were covered on all sides with a fineplastic mesh, but with the leaf petiole intact and still attached to theplant to allow normal vascular movement and photosynthesis. The plantswere then infested with 20-30 aphids (radish) or 20 leafhoppers (bean)and held in the growth chamber for 8 additional days. Each test unit wasthen visually assessed for mortality of the insects, which had contactedand fed on the untreated plant tissues.

Results of green peach aphid mortality (% GPA M) and potato leafhoppermortality (% PLH are listed in Table A.

TABLE A Percent Insect Mortality Compound % PLH M % GPA M 1 58 87 3 9681 4 93 78 5 96 94 6 77 100 26 73 67 27 13 57

Test I

For evaluating movement of compounds in plants and control of greenpeach aphid (Myzus persicae) and potato leafhopper (Empoasca fabae)after xylem movement of compound from soil application up through rootsinto foliage, the test unit consisted of a small open container with a12-15-day-old radish plant (for green peach aphid test) or 5-6-day-oldLongio bean plant (for potato leafhopper test).

Test compounds were formulated using a solution containing 10% acetone,90% water and 600 ppm X-77® Spreader Lo-Foam Formula non-ionicsurfactant containing alkylarylpolyoxyethylene, free fatty acids,glycols and isopropanol (Loveland Industries, Inc.). The formulatedcompounds were applied in 1 mL of solution by pipet to the soil at thebase of the plant. All experimental compounds in this screen wereapplied at 1000 ppm, and the tests were replicated three times. Afterapplying the formulated test compounds, each test unit was allowed todry for 1 h. The soil of each test unit was covered with a layer of sandand then a black, screened cap was placed on top. The test units wereheld in a growth chamber at about 20° C. and 50-70% relative humidity.

After 2 days, the plants were then infested with 20-30 aphids (radish)or 20 leafhoppers (bean) and held in the growth chamber for 5 additionaldays. Each test unit was then visually assessed for mortality of theinsects, which had contacted and fed on the untreated plant foliage.

Results of green peach aphid mortality (% GPA M) and potato leafhoppermortality (% PLH M) are listed in Table B.

TABLE B Percent Insect Mortality Compound % PLH M % GPA M 1 100 64 2 5664 5 95 40 6 100 59

What is claimed is:
 1. A method for controlling an invertebrate pest ofthe order of Lepidoptera or Homoptera, comprising contacting theinvertebrate pest or its environment with a biologically effectiveamount of a compound of Formula 1, an N-oxide or a salt thereof

wherein: R¹ is Me, Cl, Br or F; R² is F, Cl, Br or C₁-C₄ haloalkoxy; R³is F, Cl or Br; R⁴ is H; C₁-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₄ alkynyl,C₃-C₅ cycloalkyl, or C₄-C₆ cycloalkylalkyl, each optionally substitutedwith one substituent selected from the group consisting of halogen, CN,SMe, S(O)Me, S(O)₂Me, and OMe; R⁵ is H or Me; R⁶ is H, F or Cl; and R⁷is H, F or Cl.
 2. A method for controlling an invertebrate pest of theorder of Lepidoptera or Homoptera, comprising contacting theinvertebrate pest or its environment with a biologically effectiveamount of a composition comprising a compound of Formula 1, an N-oxideor a salt thereof

wherein: R¹ is Me, Cl, Br or F; R² is F, Cl, Br or C₁-C₄ haloalkoxy; R³is F, Cl or Br; R⁴ is H; C₁-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₄ alkynyl,C₃-C₅ cycloalkyl, or C₄-C₆ cycloalkylalkyl, each optionally substitutedwith one substituent selected from the group consisting of halogen, CN,SMe, S(O)Me, S(O)₂Me, and OMe; R⁵ is H or Me; R⁶ is H, F or Cl; and R⁷is H, F or Cl; and at least one additional component selected from thegroup consisting of a surfactant, a solid diluent and a liquid diluent;provided that the method is other than a soil drench.
 3. The method ofclaim 1 wherein the compound of Formula 1 is3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-pyrazole-5-carboxamide.4. The method of claim 2 wherein the compound of Formula 1 is3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-pyrazole-5-carboxamide.5. The method of claim 2 wherein the surfactant is selected from thegroup consisting of polyethoxylated alcohols, polyethoxylatedalkylphenols, polyethoxylated sorbitan fatty acid esters, dialkylsulfosuccinates, alkyl sulfates, alkylbenzene sulfonates,organosilicones, N,N-dialkyltaurates, lignin sulfonates, naphthalenesulfonate formaldehyde condensates, polycarboxylates, andpolyoxyethylene/polyoxypropylene block copolymers.
 6. The method ofclaim 5 wherein the surfactant is a polyoxypropylene/polyoxyethyleneblock copolymer.